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Kathleen Collins, an Associate Professor of Internal Medicine at the University of Michigan, and the Lead Author of a Study published in the journal, Nature Medicine said, “We found there was evidence that HIV in fact, does infect the bone marrow progenitor cells or parent cells that are the source of all of the different blood lineages in the body and moreover that HIV can take on a latent form and so we were able to detect the presence of virus ending cells even after patients had been on therapy for years”.

WASHINGTON — The virus that causes AIDS can hide in the bone marrow, avoiding drugs and later awakening to cause illness, according to new research that could point the way toward better treatments for the disease.

Finding that hide-out is a first step, but years of research lie ahead.

Dr. Kathleen Collins of the University of Michigan and her colleagues report in this week's edition of the journal Nature Medicine that the HIV virus can infect long-lived bone marrow cells that eventually convert into blood cells.

The virus is dormant in the bone marrow cells, she said, but when those progenitor cells develop into blood cells, it can be reactivated and cause renewed infection. The virus kills the new blood cells and then moves on to infect other cells, said.

"If we're ever going to be able to find a way to get rid of the cells, the first step is to understand" where a latent infection can continue, Collins said.

In recent years, drugs have reduced AIDS deaths sharply, but patients need to keep taking the medicines for life or the infection comes back, she said. That's an indication that while the drugs battle the active virus, some of the disease remains hidden away to flare up once the therapy is stopped.

One hide-out was found earlier in blood cells called macrophages. Another pool was discovered in memory T-cells, and research began on attacking those.

But those couldn't account for all the HIV virus still circulating, Collins said, showing there were more locations to check out and leading her to study the blood cell progenitors.

Finding these sources of infection is important because eliminating them would allow AIDS patients to stop taking drugs after their infection was over. That's critical in countries where the treatment is hard to afford and deliver.

"I don't know how many people realize that although the drugs have reduced mortality we still have a long way to go," Collins said in a telephone interview. "That is mainly because we can't stop the drugs, people have to take it for a lifetime."

The research was funded by the National Institutes of Health, Burroughs Wellcome Foundation, University of Michigan, Rackham Predoctoral Fellowship, National Science Foundation and a Bernard Maas Fellowship.

Human Immunodeficiency VirusImage: Wikimedia commons, NIAID The findings suggest the virus can hide in an inactive state for long periods of time, evading treatment, even in individuals without detectable viral loads.

"It's a little bit surprising to see that [HIV infects] progenitor cells, and [possibly] stem cells as well," said virologist Michael Bukrinsky of The George Washington University in Washington, DC, who was not involved in the research. It's a "novel and important" discovery that "will have big implications for pathogenesis of the disease and potential treatment of these patients."

Even patients who respond to highly active antiretroviral therapy (HAART) can harbor undetectably low viral loads, which can be reactivated later in life to cause a resurgence of the disease. Resting T cells can conceal such latent infections, and are the only well established and characterized HIV reservoirs. But a recent study found circulating viral genomes that differ from those found in T cells, suggesting that additional reservoirs may also exist.

When virologist Kathleen Collins of the University of Michigan in Ann Arbor and her colleagues exposed hematopoietic progenitor cells (HPCs) from bone marrow to HIV, some of the cells were quickly infected and killed by the virus. The team then pushed the progenitors to differentiate -- mostly into an antigen-presenting type of white blood cell -- and saw "a dramatic increase in viral gene expression," Collins said. These results suggested that HPCs likely harbored a latent form of the virus that could be activated by cellular differentiation. In short, HPCs represented another HIV reservoir.

"To my knowledge, we are the first to find another real reservoir beyond the resting T cell," Collins said.

"It reveals another obstacle" for viral eradication, said virologist Mario Stevenson of the University of Massachusetts Medical School, who did not participate in the study. "It shows us another area that we have to target in order to achieve a cure."

The researchers further confirmed the ability of HPCs to carry a latent infection by identifying HIV in the bone marrow in about 40 percent of patients who had undetectable viral loads for at least 6 months.

In order for cells to be able to maintain the latent virus for long periods of time, Collins said, they must live long enough to survive years of HAART. The discovery of latent infection in HPCs is "suggestive" that the new reservoir may be hematopoietic stem cells, which "we carry for our entire lives," she said. Furthermore, as stem cells have the capacity to self renew, the virus could spread through cell division, Collins added.

However, because of the type of HIV that persisted in HPCs, "I have my doubts of the functionality of these cells as reservoirs," Bukrinsky said. The HPCs infected by HIV predominately expressed chemokine receptor CXCR4, meaning they could only be infected by viruses that bind specifically to that receptor. These forms of the virus generally appear much later in infection than the major CCR5-binding viruses, which are primarily involved in transmission from one person to another, meaning the HPC reservoirs would not likely contribute to the spread of the virus through the population.

On the other hand, he added, because "CXCR4 viruses are more pathogenic than CCR5 [viruses], and HPCs are rapidly killed by the [activated] virus, patients will have some problems, even on HAART treatment, generating new T cells and macrophages."

"It all depends on the numbers," Bukrinsky said -- specifically, "the real percentage of these cells" that maintain a latent infection. With only nine patients in this study, it is unclear how frequently these cells harbor the infection. "This needs to be expanded to a bigger population to generate information about the importance of these reservoirs."

Furthermore, there may be additional reservoirs not yet identified, Stevenson said. "I think this study is going to generate a lot of interest," he said. "Whether it's the end of the story, I very much doubt it."

HIV-Infected Postmenopausal Women at High Risk for Bone Fractures - pdf publication attached- (01/11/09)JCEMConclusion: The lower BMD, higher prevalence of l ow BMD, and higher levels of bone turnover markers detected in HIV+ postmenopausal minority women could place them at high risk for future fractures.

"HIV infection was independently associated with lower bone mineral density after adjusting for body mass index (BMI) and traditional osteoporosis risk factors," said Yin. "While the reason for HIV-associated bone loss remains unclear, it may be related to increased levels of cytokines (proteins produced by cells that aid communication between cells), direct effects of antiretrovirals on bone cells or hormonal/nutritional de ficiencies that are common in HIV."

"Estrogen protects against the effect of cytokines on bone resorption," said Yin. "Therefore, as HIV-positive women become estrogen deficient during menopause, they may be at higher risk for accelerated bone loss and fracture."

--------------------------------------------------------------------------------"In conclusion, low BMD was more common in postmenopausal HIV+ than HIV- minority women. HIV infection was independently associated with lower BMD after adjusting for BMI and traditional osteoporosis risk factors. BTMs (bone turnover markers) and TNFa were higher in HIV+ ART+ women, and multivariate modeling suggested that they may mediate the effect of HIV on BMD. Completion of the ongoing longitudinal study should permit assessment of whether increased bone turnover associated with ART translates into accelerated bone loss and increased fracture rates in aging postmenopausal women."

From Xconomy.Com / March 15, 2010 E-mail this article To: Invalid E-mail address Add a personal message:(80 character limit) Your E-mail: Invalid E-mail address Sending your articleYour article has been sent. E-mail| Print| Reprints| Yahoo! Buzz| ShareThisText size – + Venture capitalists are giving the risky field of gene therapy a new dose of confidence — and cash. Genetix Pharmaceuticals, a 17-year-old developer of gene therapies, has replenished its coffers with a $35 million Series B round of venture capital.

The Cambridge-based company attracted the fresh capital after a study in France showed that one of the firm’s gene therapies blocked the progression of a debilitating brain disorder called adrenoleukodystrophy, or ALD, in two children. This is the disease that was featured in the acclaimed 1992 film “Lorenzo’s Oil,’’ the true story of a husband and wife who searched for a cure for their son with the crippling illness. While much testing will be required to bring the gene therapy to market, Boston’s Third Rock Ventures and Cambridge-based biotech giant Genzyme were convinced that there was enough promise in the data to make big bets on the company.

Third Rock and Genzyme Ventures, the venture unit of Genzyme, are the new investors in Genetix’s second-round financing, according to the company. The round includes investments from the firm’s previous VC backers Easton Capital, Forbion Capital Partners, and TVM Capital. The new funding came with major management changes at Genetix: Third Rock partner Nick Leschly is leading the firm as interim president; Phil Reilly, a venture partner at Third Rock, has become chief medical officer; and Mitchell Finer, a veteran biotech executive, is the new chief scientist. Genetix’s chief executive, Alfred Slanetz, is leaving the firm.

Gene therapies, which typically use viruses to deliver healthy genes into cells to treat diseases, have never been approved for the market nor lived up to the hype they initially generated about two decades ago. Genetix is one example of renewed faith in the science in some scientific and investor circles. The company, one of hundreds like it that formed in the 1990s to develop gene therapies, was recapitalized in 2004 and licensed technology from the French National Institute for Health and Medical Research. The French scientists who developed that technology have generated headlines around the world for its use to cure ALD in two high-profile cases.

“We’re at that same point that we were with monoclonal antibodies 12 to 15 years ago,’’ Finer, Genetix’s new chief scientific officer, says. “You look and see the resurgence of gene therapy data. We are poised to capitalize on those advancements.’’

Genetix, which has now closed $75 million in funding since its inception, adds its own twist to gene therapy. Rather than injecting its therapies directly into patients, the company treats patients’ own bone marrow after it has been extracted from them. Once the firm’s treatments have corrected the genes in patients’ bone marrow stem cells, the cells are infused back into the patients to cure their illness. To deliver healthy genes to cells, the company uses viruses derived from deactivated HIV that are designed to die off after their job is done.

March 15, 2010 | Comments: 0 Recommended this article (2) CYTX Print Share Last week, Cytori Therapeutics (CYTX - Analyst Report) was notified by the U.S. FDA that they will be required to conduct a clinical program prior to final approval of its Celution System. This was in-line with our expectations. Management plans to meet with the FDA in the next few months to discuss the requirements necessary for the Pre-Market Approval (PMA) program.

Assuming the meeting takes place this second quarter, Cytori should be in position to file the investigation device exemption (IDE) and initiate the program by the end of the year. Our best guess is that the FDA will require Cytori to conduct a 12-month study in approximately 100 patients looking at endpoints similar to the RESTORE-2 program conducted in Europe, including graft retention, patient and physician satisfaction and safety. If all goes smoothly, data should be available during the first half of 2012.

The filing could take place mid-2012. Therefore, we could be looking at a U.S. launch of the Celution System in 2013, with an indication for soft tissue filling and aesthetic body contouring in cosmetic and reconstructive surgery.

In the meantime, Cytori plans to ramp sales of its PureGraft product in the U.S. as a gateway product into the plastic surgery market. PureGraft is a low entry price, but high margin, useful tool that helps drive awareness and Cytori’s presence as a major player in aesthetic body contouring. The product compliments the Celase (Cytori’s proprietary enzyme product) and Celbursh (Cytori’s graft delivery instrument) products available for cosmetic and reconstructive procedures.

Ex-U.S. Market Key

The cosmetic surgery market outside the U.S. remains the key driver of revenues given the lack of reimbursement issues and growing movement toward the use of fat tissue procedures. We note that a direct sales model is the best strategy to target physicians and customers in the area of aesthetic body contouring, so management has become more active in the marketing and distribution of Celution around Europe and Asia.

Support for fat grafting procedures using Cytori’s Celution System has been growing nicely since the release of the interim data from the RESTORE-2 program in San Antonio in December 2009. Data at the San Antonio Breast Cancer Symposium, along with recent data at the Miami Breast Cancer Symposium in March 2010, demonstrated high patient and physician satisfaction, along with objective endpoints in both breast defect and overall breast shape post reconstruction.

In the above investigator-initiated studies for reconstruction, cell-enriched fat grafting with Cytori’s Celution System was safe and generally improved breast deformities and quality of life. Plus, the technique can be used alone or with other forms of breast reconstruction, including in reconstruction with implants.

We think these results bode very well for the future of cell-enriched breast reconstruction and Cytori’s Celution CRS System. We expect this to ramp significantly in the next few quarters as awareness, familiarity and reimbursement improve.

Expanding Cytori's Use?

Beside the progress being made in cosmetic and reconstructive surgery, Cytori is looking to expand the development of new applications for Celution System. In 2009, enrollment was completed in two cardiovascular disease trials, both of which met key end-points of safety and feasibility. The APOLLO trial (n=14) treated patients with acute myocardial infarction or heart attack. The PRECISE trial (n=27) included patients suffering from chronic myocardial ischemia.

Importantly, the trials demonstrated that physicians were able to safely extract a meaningful volume of adipose tissue, separate and concentrate the stem and regenerative cells using the Celution System and deliver these cells into the heart during the same interventional procedure.

Management noted that investigators in APOLLO saw an average 45% reduction in perfusion defect size at six month in the first five of the 13 patients testing, and although the data is still blinded, and 4 of the 13 patients are on placebo, this significant reduction in defect size is clearly far beyond what should normally be expected in this post-major heart attack population.

Our guess is that a pivotal program in approximately 250 patients will be necessary for a marketing claim with Celution for use in an acute MI population. This could begin in 2011. Outcomes from both of these studies will be reported on May 7, 2010 at the Seventh International Symposium on Stem Cell Therapy and Cardiovascular Innovations in Madrid, Spain. Additional studies are planned or underway including peripheral vascular disease, heart failure, liver insufficiency, kidney ischemia, burn scar adhesions, HIV facial wasting, wrinkle therapy, GvHD, and others.

In Korea, the term “stem cell” conjures up unhappy memories of Dr. Hwang Woo-suk, the cloning scientist who was crowned as a national hero back in 2004 only to be disgraced when it was revealed that much of his work had been fraudulent.

Yet even that national trauma didn’t damage the reputation of those two magic words, which now are being used to sell cosmetics. Makeup and skin products using stem cell-derived ingredients are already on the market, in fact.

Korean authorities have long harbored doubts about the safety of these products - but they haven’t decided just what to do about it yet.

In March last year, the Korea Food and Drug Administration was ready to propose a prohibition on the use of any material originating from human stem cells in cosmetics. The list of materials to be banned included stem cell culture fluid, as the agency said materials extracted from human cells could spread HIV or hepatitis viruses.

The measure would have removed from store shelves all cosmetics made from stem cells. Although stem-cell culture fluid is in the “International Cosmetic Ingredient Dictionary and Handbook,” which lists labeling names for the United States, the European Union and other countries, the KFDA was certain the fluid had safety issues.

In November, however, the agency softened its stringent stance, removing culture fluid from the banned list along with new regulations on cosmetics ingredients. Industry insiders said the government’s reversal came after harsh protests from cosmetics developers and manufacturers, who consider the ingredients a “new growth engine.”

Yet it wasn’t a blank check. The KFDA told cosmetics firms and consumers it would develop new regulations for stem cell cosmetics by June 2010. “Rather than entirely prohibiting [stem cell-related cosmetics], laying out safety rules seems like a better idea, given the attention [they attract] in the cosmetics communities at home and abroad,” read a KFDA statement released at the time.

That deadline won’t be met. A high-ranking official with the KFDA, part of the Health Ministry, said regulators are now “trying our best to make it by the year’s end.”

The official, who asked not to be named, said, “We don’t know for sure what’s in the stem cell culture fluid, and the culturing process leaves room for viral infection. It’s impossible that there are no problems with the material.”

Asked why the regulations are being delayed, the official only said, “We are now working on measuring sticks to guarantee [the cosmetics’] safety. It takes a sizable amount of time to review the technical feasibility of these measuring sticks.”

Despite Hwang’s fall from grace, products with the words “stem cell” on them still enjoy a halo effect on the Korean market, and “stem cell cosmetics” has emerged as a buzz phrase in the local beauty industry, particularly in the past two years. Promising to help fight the aging process and even revive youthful skin, the controversial beauty products are quickly gaining traction in the world’s seventh-largest cosmetics market.

RNL Bio, a Seoul-based biotech firm, launched what they call the country’s first stem cell cosmetics early last year. The company, which gained fame in 2008 for cloning a pit bull terrier at the request of an American woman whose dog had died, named the product “Dr. Jucre,” short for “Juvenescence Creation with Cell Regeneration.” Consisting of serum, cream and a sheet mask, Dr. Jucre started making house calls in the United States last August, and an RNL spokeswoman, Kim Yoon, said the line will hit shelves at major department stores in Seoul in the coming weeks.

Other local biotech ventures such as Histostem, Prostemics and BioSpectrum have followed in RNL’s footsteps, marketing stem cell-derived products that range in price from 100,000 won ($88) to millions of won. A flurry of smaller, low-profile enterprises and private hospitals are also involved in the burgeoning business. But the industry remains a statistical blind spot - no private or government figures on the size of the market, the number of companies or the consumer demographics are currently available.

Despite the name, no “stem cell cosmetics” actually contain human cells. Using actual human stem cells in cosmetics has never been allowed in Korea due to the potential risk of infection. The same is true in the United States and the EU.

In the majority of cases, the new cosmetics are comprised of conventional anti-aging agents derived from marine and botanical products, along with stem cell culture fluid - liquid that has been used to culture stem cells but does not actually contain any human tissue.

Actual stem cells are quite potent. As the only human cell capable of differentiating into many different types - into part of the liver or kidney, say - they could help repair the body by repairing otherwise irreversible damage to internal organs caused by disease or injury.

Adult stem cells, as opposed to the variety derived from embryos, which is not used for cosmetics, are usually extracted from fat tissue removed in liposuction surgery at hospitals. Some cosmetics producers take them from human umbilical cords. The companies say they have patients sign release forms to use the cells.

But where stem cells themselves may have a seemingly miraculous medical potential, stem cell culture fluid is still unproven. The companies say that stem cells discharge “cell growth chemicals” as they grow in the culture fluid, which gives their products the ability to slow the aging process and improve elasticity. The firms claim the substances are innovative enough to replace even such well-established treatments as retinol, a type of vitamin A, and the exfoliating agent glycolic acid.

Most stem cell cosmetics manufacturers cite clinical tests of up to 25 weeks that they say prove their products are highly effective in reducing wrinkles and boosting skin moisture and elasticity. They also cite documentation guaranteeing no health risks, though the validity of all these claims are often unverifiable.

But some others provide little more than flowery words. One company’s Web page depicts stem cells extracted from human umbilical cord blood as “a noncontroversial source of stem cells derived from nature’s own river of eternal youth.” When asked about stem cell cosmetics over the phone, a worker at the company said, “Since it’s not a chemical product, there should hardly be any side effects. If you discover red spots and rashes after testing it on the back of your hand, stop using it.”

Medical experts are suspicious of both the health risks and effectiveness of these wonder products. “Whether it’s cosmetics or medicine, any clinical test period is supposed to be lengthy. It’s too early for stem cell cosmetics producers to say their products have no health risks after testing them for less than a year. Infection through topical application is highly possible, even if problems have yet to arise since these products have been out for only two years,” said Dr. Oh Il-hoan, a professor at the Catholic University of Korea’s medical school. For example, Oh said, one medicine used to treat degenerative arthritis underwent clinical testing for four years, and when problems arose in the fourth year the entire project was scrapped.

“I can see that the state health watchdog is in a very hard place. On one side, it needs to encourage stem cell businesses, but on the other side it has lingering doubts about their safety. [The KFDA] has no choice but to be politically affected by the commercial sector,” Oh added.

Perhaps even worse for such potentially risky materials, no stem cell cosmetic product has yet been officially recognized for its anti-aging function, according to the KFDA. Another KFDA official, who also requested anonymity, said, “None of the so-called stem cell cosmetics out on the market have scientifically proven to us their effectiveness.”

Dr. Oh mused, “I’m afraid consumers are paying extra costs for effects that don’t exist. Even if the products show visible effects in the short term, nobody can guarantee if they will cause side effects later.”

Lee Ju-hong, a spokesman with the nonprofit Green Consumers Network in Korea, pointed out a more fundamental issue. “Basically, the KFDA is saying it wants to give more autonomy to those stem cell cosmetics producers and punish them if any issue erupts later. That is what the United States is doing,” he said.

But under the Korean legal structure, which is based on European law and emphasizes preliminary regulation, the KFDA loses its chance to penalize companies heavily once their products go to market. Korean law does not allow harsh punitive measures for companies causing consumer damage like U.S. law does, according to Lee.

The network spokesman continued, “The most desirable scenario would be for the government and cosmetics producers to quickly join together and come up with guidelines on stem cells in cosmetics. The government should not repeat its practice of issuing a prescription after the patient’s death.”

CROI: Inflammation/activation linked to diseases of organ systems (heart, kidney, liver) & death in USA and now reported as well in Africa - HIV accelerated aging will be bigger problem in undeveloped countries

"New data presented at CROI 2010 further confirm the importance of chronic inflammation in the pathogenesis of non-AIDS complications of HIV infection, even in those successfully treated with ART. Despite some intriguing hints into the pathogenesis and treatment of chronic inflammation provided at this conference, the cause remains unclear and is likely multifactorial."Chronic Inflammation in HIV: CROI 2010 - written by David H Shepp, MD Associate Professor of Medicine, Hofstra University School of Medicine Division of Infectious Diseases, North Shore University Hospital-Manhasset - (03/03/10)

"In aggregate, these studies provide evidence that ongoing HIV replication is unlikely to explain chronic inflammation but leave the door open to a possible benefit from intensification therapy via reduced immune activation. the link between chronic inflammation and CVD has been more thoroughly investigated, chronic inflammation appears to have an association with disease in other organ systems with overall mortality in HIV-infected persons. CRP and fibrinogen levels at baseline were strongly correlated with subsequent mortality. Baseline levels of either marker in the highest tertile were associated with about a 2.6-fold increased risk of death. The effect of elevated CRP or fibrinogen on mortality was significant across all levels of CD4, from <200 to >500. An analysis of non-AIDS mortality data from the SMART study suggested co-infection with HCV or HBV creates and especially dangerous proinflammatory state that strongly predisposes to death in the absence of continuous ART. For patients in SMART with elevated HA plus an increased level of any of the 3 biomarkers, the adjusted hazard ratio for death increased 4.4-6.1-fold compared to those with normal levels of HA and the biomarker. Gupta et al.8 reported a small pilot study to define urinary markers of kidney inflammation in patients with HIV and proteinuria but without other known conditions predisposing to proteinuria. Compared to HIV+ but non-proteinuric controls, urinary levels of two inflammatory cytokines, MCP-1 and RANTES (assessed by cytokine/creatinine ratio) were elevated. Another hypothesized cause of chronic immune activation is persistent viral coinfection, VGCV treatment suppressed CMV infection and reduced CD8+ activation markers significantly when compared to placebo. Patients who initiated ART during acute or early HIV infection in the OPTIONS study were compared to patients in the SCOPE cohort who initiated in the chronic phase when CD4 was less than 350. Arterial stiffness associated with traditional CVD risk factors and after adjustment, with a nadir CD4 <350."

CROI: Rapid Progression of Atherosclerosis at the Carotid Bifurcation Is Linked to Inflammation in HIV-infected Patients - "These data strongly suggest that inflammation contributes to the higher risk of atherosclerosis noted in HIV-infected persons." - (02/22/10)Elite controllers, without ART or viremia, have more rapid IMT progression compared to controls

CROI:Inflammation Is Associated with Endothelial Dysfunction Among Individuals with Treated and Suppressed HIV Infection - (02/26/10)

improvements in TNF-alpha, sTNFr, IL-2, IL-6, IL-8, and IL-17 in the first 12 weeks predicted better 24- and 48-week CD4 and virologic outcomes. The ACTG team concluded that assignment to immediate versus deferred antiretroviral therapy did not affect CD4 or viral load response at week 24 or 48. But they proposed that inflammation in the first 12 weeks of treatment for opportunistic diseases and bacterial infection affects 24- and 48-week CD4 and viral load--regardless of treatment assignment.

CROI:Early Antiretrovirals in People Diagnosed With AIDS May Quell Inflammation Faster -- (02/25/10)

CROI:Risk of Non-AIDS Death in HIV/HCV-Coinfected People in SMART - - (03/01/10)The SMART investigators proposed that, among people coinfected with HIV and a hepatitis virus, "those with impaired liver function are particularly in a pro-inflammatory state associated with excess risk of death from causes other than AIDS--and interruption of ART further exacerbates this pro-inflammatory state."

CROI: Plasma Levels of Soluble CD14 (activation marker) Predict Mortality in HIV Infection - (03/05/10)we investigated the relationship of baseline biomarkers of microbial translocation with all-cause mortality. Among patients with HIV infection, greater monocyte responsiveness to LPS, exhibited by high sCD14 levels, is associated with all-cause mortality, but other biomarkers of microbial translocation are not related to all-cause mortality. Patients in the highest quartile of LPS bioactivity, with sCD14 levels >2.71x106 pg/mL, had an OR of death of 6.0 versus the lowest quartile with levels <2.01x106 pg/mL (see table).

CROI: Effect of the Intensification with a CCR5 Antagonist Maraviroc on the Decay of the HIV-1 Latent Reservoir and Residual Viremia - reduced activation - (03/04/10)In this preliminary analysis, intensification with MVC seems to accelerate the decay of the HIV latent reservoir. Unexpectedly, an increase in RV measured by SCA and episomal 2-LTRs DNA detection has been observed. A decrease in the activation of CD4 and CD8 cells was observed at wk12 of intensification.

CDC Analysis Provides New Look at Disproportionate Impact of HIV and Syphilis Among U.S. Gay and Bisexual Men

CDC Press Release March 10 2010

A data analysis released today by the Centers for Disease Control and Prevention underscores the disproportionate impact of HIV and syphilis among gay and bisexual men in the United States.

The data, presented at CDC's 2010 National STD Prevention Conference, finds that the rate of new HIV diagnoses among men who have sex with men (MSM) is more than 44 times that of other men and more than 40 times that of women.

The range was 522-989 cases of new HIV diagnoses per 100,000 MSM vs. 12 per 100,000 other men and 13 per 100,000 women.

The rate of primary and secondary syphilis among MSM is more than 46 times that of other men and more than 71 times that of women, the analysis says. The range was 91-173 cases per 100,000 MSM vs. 2 per 100,000 other men and 1 per 100,000 women.

While CDC data have shown for several years that gay and bisexual men make up the majority of new HIV and new syphilis infections, CDC has estimated the rates of these diseases for the first time based on new estimates of the size of the U.S. population of MSM. Because disease rates account for differences in the size of populations being compared, rates provide a reliable method for assessing health disparities between populations.

"While the heavy toll of HIV and syphilis among gay and bisexual men has been long recognized, this analysis shows just how stark the health disparities are between this and other populations," said Kevin Fenton, M.D., director of CDC's National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. "It is clear that we will not be able to stop the U.S. HIV epidemic until every affected community, along with health officials nationwide, prioritize the needs of gay and bisexual men with HIV prevention efforts."

For the purposes of determining rates of disease for MSM, CDC researchers first estimated the size of the gay and bisexual male population in the United States – defined as the proportion of men who reported engaging in same-sex behavior within the past five years. Based on an analysis of nationally representative surveys, CDC estimated that MSM comprise 2.0 percent (range: 1.4-2.7 percent) of the overall U.S. population aged 13 and older, or 4 percent of the U.S. male population (range: 2.8-5.3 percent). Disease rates per 100,000 population were then calculated using 2007 surveillance data on HIV and primary/secondary syphilis diagnoses and U.S. Census data for the total U.S. population.

The new analysis is the first step in more fully assessing the impact of HIV among MSM and other populations significantly affected by the disease. CDC is developing more detailed estimates of infection rates among MSM by race and age, as well as among injection drug users. CDC is also in the early stages of planning for estimates among heterosexuals. Ultimately, these data can be used to better inform national and local approaches to HIV and STD prevention to ensure that efforts are reaching the populations in greatest need.

Research shows that a range of complex factors contribute to the high rates of HIV and syphilis among gay and bisexual men. These factors include high prevalence of HIV and other STDs among MSM, which increases the risk of disease exposure, and limited access to prevention services. Other factors are complacency about HIV risk, particularly among young gay and bisexual men; difficulty of consistently maintaining safe behaviors with every sexual encounter over the course of a lifetime; and lack of awareness of syphilis symptoms and how it can be transmitted (e.g., oral sex). Additionally, factors such as homophobia and stigma can prevent MSM from seeking prevention, testing, and treatment services.

Also, the risk of HIV transmission through receptive anal sex is much greater than the risk of transmission via other sexual activities, and some gay and bisexual men are relying on prevention strategies that may be less effective than consistent condom use.

"There is no single or simple solution for reducing HIV and syphilis rates among gay and bisexual men," said Fenton. "We need intensified prevention efforts that are as diverse as the gay community itself. Solutions for young gay and bisexual men are especially critical, so that HIV does not inadvertently become a rite of passage for each new generation of gay men."

Preventing HIV and STDs among gay and bisexual men is a top CDC priority. CDC provides funding to health departments and community-based organizations throughout the nation to implement proven behavior-change programs for MSM and will soon expand a successful HIV testing initiative to reach more gay and bisexual men. Additionally, CDC is implementing an updated National Syphilis Elimination Plan in cities where MSM have been hardest hit by the disease, and will release an updated HIV prevention strategic plan within the next year to support the President's upcoming National HIV/AIDS Strategy. CDC officials note that the new analysis released today underscores the importance of the HIV and STD prevention efforts targeting gay and bisexual men recently announced as part of the President's fiscal year 2011 budget proposal.

Collectively, these observations are consistent with a model in which untreated HIV infection results in immune activation, accelerated immunologic aging and the emergence of a population of potentially dysfunctional immunosenescent T cells. Antiretroviral therapy-mediated suppression of HIV replication may only partially reverse or prevent this process. The presence of a large population of activated and/or senescent T cells may be causally associated with the premature onset of CVD.

SUMMARY OF RESULTS/DISCUSSION

Consistent with prior data, HIV infection was associated with markedly elevated levels of activated (CD38+HLA-DR+) peripheral T-cells. Viremic suppression through effective antiretroviral therapy appeared to reduce but not completely reverse this process.

Among HIV-infected women, T-cell activation was associated with markers of subclinical carotid artery disease after adjustment for multiple confounders. Among HIV-infected women, CD8+ T-cell senescence, and to a lesser extent CD4+ T-cell senescence (phenotypically defined by absence of CD28 and presence of CD57), were also associated with HIV disease and with the presence subclinical carotid artery disease.

These associations of T-cell activation and senescence with carotid artery parameters were not observed in a population of HIV-uninfected controls who were studied using identical methods and who had comparable cardiovascular risk factor profiles. Relatively small sample size of the HIV-uninfected group is a limitation.

ABSTRACT

HIV infection results in chronic elevated T cell activation and inflammation. This inflammatory state is reduced but not normalized by antiretrovirial therapy. Among treated patients, inflammatory markers are associated with risk of death and cardiovascular events. In HIV seronegative individuals, inflammation may be associated with accelerated immunologic aging (immunosenescence). The degree to which immunosenescence exists during treated HIV infection, and the impact of this process on cardiovascular disease has not been defined.

(from Jules: Carotid distensibility (CD) is a measure of carotid artery elasticity that has been introduced as a risk factor for cardiovascular disease. Morphological studies have indicated that arterial distensibility depends on different factors such as blood pressure and age. Aging is the main variable responsible for functional changes in the arterial wall leading to an increase in arterial stiffness)â€¨.

RESULTS

The mean age of the HIV-infected and unifected women were 46.6 and 47.2 years, respectively. Most subjects were on HAART (n=66) and many had undetectable viral loads (n=28).

As compared to the HIV uninfected subjects, the treated women with undetectable viral loads had higher levels of CD4 T-cell activation (p<.01) and CD8 T-cell activation (p<.02); CD8+ T cell senescence (p=0.07) but not CD4+ T cell senescence (p=0.53) also tended to be increased in the treated aviremic women.

Similarly, carotid lesions were significantly increased among HIV-infected women with CD4+ T-cell count<200 as compared with controls, and among the HIV-infected subjects there was an association of T-cell activation and senescence with the presence of carotid lesions.

Given the evidence that HIV infection may be associated with premature onset of age-related diseases, we investigated the effect of untreated and treated HIV on T-cell immunosenescence. We also investigated the impact of T-cell activation and senescence on subclinical carotid artery disease measured by B-mode ultrasound.

2. SUBJECTS

The study was conducted among participants in the Womenâ€™s Interagency HIV Study (WIHS), prospective multicenter study conducted at 6 US centers.

Characteristics of HIV-infected and HIV-uninfected women.

*over duration of study enrollment. For subjects who entered the study on HAART, peak plasma HIV RNA and nadir CD4 counts were also obtained by chart review.

Funding: Funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD-32632), and co-funded by the National Cancer Institute, the National Institute on Drug Abuse, the National Institute on Deafness and Other Communication Disorders, the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131), the National Heart, Lung and Blood Institute (1R01HL095140, 1R01HL083760 to Albert Einstein), NIH/NIAID funding to the UCSF-GIVI Center for AIDS Research (P30AI027763) and NCR funding to the UCSF Clinical and Translational Science Institute (UL1RR024131).

...HCV-positive viremic women with HIV coinfection who have high levels of T cell activation may have increased risk of AIDS...

....In adjusted generalized estimating equation models, percentage of CD8+CD38+DR+ T cells was statistically significantly positively associated with HCV status (p=.04). Other independent correlates of CD8 activation included HIV RNA level and ART.......HCV-positive viremic women were more likely to have bacterial pneumonia (20% vs 13%; p=.002 ), dementia and/or encephalopathy (11% vs 7%; p=.02), and wasting syndrome (12% vs 8%; p=.03) than were HCV-negative women.....HCV-positive viremic women were more likely to develop AIDS with an HCV RNA level of >2.3 million IU/mL.....and were more likely to die an AIDS-related death with an HCV RNA level of >3.98 million IU/mL...

....Immune activation has been closely linked to HIV disease progression [1, 4, 5, 34-36], but to our knowledge this association has not previously been reported in the setting of HCV coinfection....

.....our findings from this large cohort study, which included 1307 women, are notable: HCV coinfection was associated with increased CD8 activation. Finally, our most important finding was the statistically significant association between the level of activated CD8 T cells and incident AIDS among HCV-positive viremic women. HCV-positive viremic women with >43% activated CD8 T cells had an almost 3-fold increased risk of AIDS-defining conditions and/or AIDS-related deaths compared with HCV-positive viremic women with <26% activated CD8 T cells. This was not found for HCV-negative women.....data suggest that the increased risk of HIV disease progression among HCV-coinfected women with high levels of CD8 activation may be due to immune dysfunction....

.....In conclusion, our study demonstrates that HIV-coinfected HCV-positive viremic women are at increased risk for AIDS-defining conditions compared with HCV-negative women, possibly because of high levels of activation of T cells, especially CD8 T cells, which indicates increased immune dysregulation in this population of women. Lower levels of activation of both CD8 and CD4 T cells and activation of CD8 T cells expressing only HLA-DR is protective against AIDS. Further study is needed to understand better the pathogenesis of T cell activation, especially of CD8 T cells in relation to HIV disease. HCV-positive viremic women may benefit from treatment of HIV and HCV infection to prevent significant immunologic changes and improve long-term outcome. Assessing CD4 and CD8 T cell activation could help clinicians evaluate their patients' risk of developing AIDS

CARLSBAD, Calif., Mar 17, 2010 (BUSINESS WIRE) -- Regulus Therapeutics Inc. announced today that the United States Patent and Trademark Office (USPTO) has allowed claims in U.S. Application Serial No. 11/977,506 covering methods of antagonizing miR-181a to regulate immune response. This patent is owned by Stanford University and licensed exclusively to Regulus. miR-181a has been shown to regulate the response of immune cells, such as T lymphocytes, to specific stimuli and modulation of miR-181a could lead to a novel treatment of inflammatory disease.

"We are pleased with the decision of the USPTO to allow this first application based on the Li et al. patent filing. We are applying our expertise in microRNA biology and nucleic acid chemistry to develop novel medicines for treating inflammatory disease, and this new allowance will expand the scope of our exclusivity surrounding the anti-miR approach to miR-181a," said Garry E. Menzel, Ph.D., Executive Vice President of Corporate Development and Finance of Regulus Therapeutics. "More broadly, we continue to build a robust patent portfolio that supports our strategy of developing and commercializing high-impact microRNA-based therapeutics in multiple disease areas."

Data published in 2007 by scientists at Stanford University and Alnylam Pharmaceuticals in the journal Cell [li QJ et al. 2007 Apr. 6;129(1):147-61] demonstrated that modulation of miR-181a levels in an immune cell modified the sensitivity of the cell to specific stimuli. Increased expression of miR-181a led to an increase in immune cell response to an inflammatory stimulus. Conversely, decreasing levels of miR-181a in immune cells de-sensitized the cell to the stimulus. Consistent with this observation, using an anti-miR to antagonize miR-181a function reduced immune cell response to a stimulus.

The newly allowed claims cover methods of modulating miR-181a in T cells, to raise the T cell receptor signaling threshold, and decrease the sensitivity of T cells to antigen stimulation. The claims cover the use of a broad class of anti-miRs targeting miR-181a, including anti-miRs having varying lengths and chemical modifications.

About microRNAs The discovery of microRNA in humans is one of the most exciting scientific breakthroughs in the last decade. microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression. Nearly 700 microRNAs have been identified in the human genome, and more than one-third of all human genes are believed to be regulated by microRNAs. As a single microRNA can regulate entire networks of genes, these new molecules are considered the master regulators of the genome. microRNAs have been shown to play an integral role in numerous biological processes including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development. Many microRNAs are conserved across multiple species indicating the evolutionary importance of these molecules as modulators of critical biological pathways. Indeed, microRNA expression or function has been shown to be significantly altered in many disease states, including cancer, heart failure and viral infections. Targeting microRNAs opens the possibility of a novel class of therapeutics and a unique approach to treating disease by modulating entire biological pathways.

About Regulus Therapeutics Inc. Regulus Therapeutics is a biopharmaceutical company leading the discovery and development of innovative new medicines based on microRNAs. Regulus is targeting microRNAs as a new class of therapeutics by working with a broad network of academic collaborators and leveraging oligonucleotide drug discovery and development expertise from its founding companies Alnylam Pharmaceuticals /quotes/comstock/15*!alny/quotes/nls/alny (ALNY 18.16, +0.01, +0.06%) and Isis Pharmaceuticals /quotes/comstock/15*!isis/quotes/nls/isis (ISIS 9.80, -0.07, -0.71%) . Regulus is advancing microRNA therapeutics towards the clinic in several areas including hepatitis C infection, cardiovascular disease, fibrosis, oncology, immuno-inflammatory diseases, and metabolic diseases. Regulus' intellectual property estate contains both the fundamental and core patents in the field as well as over 600 patents and more than 300 pending patent applications pertaining primarily to chemical modifications of oligonucleotides targeting microRNAs for therapeutic applications. In 2008, Regulus entered into a major alliance with GlaxoSmithKline to discover and develop microRNA therapeutics for immuno-inflammatory diseases. In 2010, Regulus entered into a new collaboration with GlaxoSmithKline to develop and commercialize microRNA therapeutics targeting microRNA-122 for the treatment of Hepatitis C Viral infection. For more information, visit www.regulusrx.com.

Forward-Looking Statements This press release includes forward-looking statements regarding the future therapeutic and commercial potential of Isis', Alnylam's and Regulus' business plans, technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus, including statements regarding the therapeutic potential of targeting miR-181a. Any statement describing Isis', Alnylam's or Regulus' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Such parties' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause their results to differ materially from those expressed or implied by such forward-looking statements. Although these forward-looking statements reflect the good faith judgment of the management of each such party, these statements are based only on facts and factors currently known by Isis, Alnylam or Regulus, as the case may be. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Regulus', Alnylam's, and Isis' programs are described in additional detail in Alnylam's and Isis' annual reports on Form 10-K for the year ended December 31, 2009. Copies of these and other documents are available from Alnylam or Isis. SOURCE: Regulus Therapeutics Inc. Regulus Therapeutics Zachary Zimmerman, Ph.D., 760-268-6811 or Media: Russo Partners Heidi Chokeir, Ph.D., 619-528-2217

Discovery of cellular 'switch' may provide new means of triggering cell death, treating disease — [16 Mar 2010] — A research team led by the University of Colorado at Boulder has discovered a previously unknown cellular 'switch' that may...

A new type of stem cells found in prostate may be involved in cancer — [9 Sep 2009] — A new type of stem cell found in the prostate of adult mice can be a source of prostate cancer, according to a new study...

Study reveals new genetic culprit in deadly skin cancer — [30 Aug 2009] — Drawing on the power of DNA sequencing, National Institutes of Health researchers have identified a new group of genetic...

New technique could eliminate inherited mitochondrial disease — [26 Aug 2009] — Researchers have developed an experimental technique with the potential to prevent a class of hereditary disorders passed...

More Health...UCLA AIDS Institute researchers successfully removed CCR5 - a cell receptor to which HIV-1 binds for infection but which the human body does not need - from human cells. Individuals who naturally lack the CCR5 receptor have been found to be essentially resistant to HIV.

Using a humanised mouse model, the researchers transplanted a small RNA molecule known as short hairpin RNA (shRNA), which induced RNA interference into human blood stem cells to inhibit the expression of CCR5 in human immune cells.

The findings provide evidence that this strategy can be an effective way to treat HIV-infected individuals, by prompting long-term and stable reduction of CCR5.

ViiV Healthcare would like to inform people that the company has a patient assistance program that can assist many patients in accessing the HIV medicines of ViiV Healthcare while they are on waiting lists for AIDS Drug Assistance Programs (ADAPs). Patients who are accepted to ADAPs are uninsured, underserved, and often learn of their HIV diagnosis at a late stage of their disease. For patients who are diagnosed with late stage disease and recommended for treatment, timely access to medicines is critical, and delays can lead to the development of life-threatening opportunistic infections.

The current economy and rising HIV infection rates have resulted in growing waiting lists for state ADAPs. As a result, patients with an HIV or AIDS diagnosis are waiting for access to life-saving medicines that may also reduce medical costs associated with uncontrolled HIV disease. According to the National Alliance of State and Territorial AIDS Directors (NASTAD), as of March 5, 2010, there were 662 individuals on ADAP waiting lists in ten states.

ViiV Healthcare believes that access to healthcare among economically disadvantaged populations, both at home and abroad, is one of the world's most pressing social challenges. Along with the HIV community, state and local government, and others, we are committed to increasing access to care.

Through Bridges to Access, ViiV Healthcare offers assistance to patients with a monthly household income below 250 percent of the federal poverty level who do not have prescription drug benefits through any insurer, payer, or program. Patients on ADAP waiting lists are considered uninsured for purposes of determining eligibility for the patient assistance program. ViiV Healthcare expects that the majority of ADAP clients on waiting lists will have incomes that will allow them to qualify for help through Bridges to Access. Individuals can find out if they qualify by visiting www.bridgestoaccess.com or by contacting ViiV Healthcare at 877-844-8872.

ViiV Healthcare believes it is critical to inform people about access to HIV medicines through patient assistance programs like Bridges to Access. We will work alongside NASTAD and other groups to ensure patients, case workers, and others involved in assisting those on ADAP waiting lists are aware that our program is available. Information about the eligibility requirements for other patient assistance programs can be found by contacting the Partnership for Prescription Assistance at 1-877-477-2669 or by visiting www.PPARx.com.

* HIV positive at 17, college freshman lost insurance* Fortis used algorithms to target HIV patients* Fortis, now Assurant, ordered to pay $10 millionBy Murray WaasWASHINGTON, March 17 (Reuters) - In May, 2002, Jerome Mitchell, a 17-year old college freshman from rural South Carolina, learned he had contracted HIV. The news, of course, was devastating, but Mitchell believed that he had one thing going for him: On his own initiative, in anticipation of his first year in college, he had purchased his own health insurance.

Lack of Interaction between Etravirine and Raltegravir plus ...A pharmacokinetic study was conducted in a subgroup of patients included in the TRIO study to evaluate these parameters. Raltegravir, darunavir, ritonavir ...www.natap.org/2010/CROI/croi_83.htm

CROI:Darunavir Penetrates Semen Well With High Levels Through 24 Hours -- (02/28/10)

Zocor (simvastatin): increased risk of muscle injury with high dosesSimvastatin is sold as a single-ingredient generic medication and as the brand-name, Zocor. It is also sold in combination with ezetimibe as Vytorin; and niacin as Simcor.Audience: Primary care providers, patients

FDA notified healthcare professionals and patients that, based on review of data from a large clinical trial and other sources, there is an increased risk of muscle injury in patients taking the highest approved dose of the cholesterol-lowering medication, Zocor (simvastatin ) 80 mg, compared to patients taking lower doses of simvastatin and possibly other drugs in the "statin" class. FDA is also reviewing data from other clinical trials, observational studies, adverse event reports, and data on prescription use of simvastatin to better understand the relationship between high-dose simvastatin use and muscle injury.

Recommendations for healthcare professionals, recommendations for patients and a data summary of information used in this ongoing review are provided in the Drug Safety Communication.

Read the complete MedWatch 2010 Safety summary, including a link to the Safety Communication and current Prescribing Information, at:

Zocor (simvastatin): increased risk of muscle injury with high dosesSimvastatin is sold as a single-ingredient generic medication and as the brand-name, Zocor. It is also sold in combination with ezetimibe as Vytorin; and niacin as Simcor.Audience: Primary care providers, patients

[Posted 03/19/2010] FDA notified healthcare professionals and patients that, based on review of data from a large clinical trial and other sources, there is an increased risk of muscle injury in patients taking the highest approved dose of the cholesterol-lowering medication, Zocor (simvastatin) 80 mg, compared to patients taking lower doses of simvastatin and possibly other drugs in the "statin" class. FDA is also reviewing data from other clinical trials, observational studies, adverse event reports, and data on prescription use of simvastatin to better understand the relationship between high-dose simvastatin use and muscle injury.

Recommendations for healthcare professionals, recommendations for patients and a data summary of information used in this ongoing review are provided in the Drug Safety Communication.

1Department of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania; 2HIV Drug Resistance Program, National Cancer Institute–Frederick, National Institutes of Health (NIH), Frederick, 3Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, and 4Clinical Research Section, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland; and 5Department of Pharmacology, University of Alabama at Birmingham, Birmingham

Results. There was no evidence in any subject of a decline in HIV‐1 RNA level during the period of raltegravir intensification or of rebound after discontinuation. Median levels of HIV‐1 RNA before (0.17 log10 copies/mL), during (0.04 log10 copies/mL), and after (0.04 log10 copies/mL) raltegravir intensification were not significantly different (p>.01 for all comparisons in parametric analyses). High‐performance liquid chromatography and mass spectroscopy experiments confirmed that therapeutic levels of raltegravir were achieved in plasma during intensification.

Conclusions. Intensification of antiretroviral therapy with a potent HIV‐1 integrase inhibitor did not decrease persistent viremia in subjects receiving suppressive regimens, indicating that rapidly cycling cells infected with HIV‐1 were not present. Eradication of HIV‐1 from infected persons will require new therapeutic approaches.

"In this study, raltegravir intensification revealed the presence of active replication in a large percentage (29%) of subjects on suppressive HAART......Our study also reveals a causal relationship between active replication and immune activation in CD8+ T cells......Longitudinal analysis showed a significant reduction in CD8+ T cell activation markers in the 2-LTR+ subgroup that was particularly evident in CD8+CD45RO+CD38+ T cells (P = 0.047, Fig. 3a). Additionally, the numbers of CD8+HLA-DR+CD45RO+ and CD8+HLA-DR+CD38+ activated cells in the 2-LTR+ subgroup were reduced over time compared to those in the 2-LTR− subgroup...there was also a trend toward a greater increase in absolute CD4+ T cell counts in the 2-LTR+ subgroup at week 24 (P = 0.085; signed rank test), with a larger increase in the percentage of CD4+CD45RA− T cells. These results strengthen the statistical conclusions drawn from the main analysis and indicate that raltegravir is more likely to affect immune activation in people showing altered 2-LTR circle dynamics. This supports the conclusion that residual viral replication, as revealed by 2-LTR circle levels, drives immune activation and that raltegravir intensification can reduce the extent of immune activation by suppressing residual viral replication

"Our study leads us to ask to what extent active replication contributes to viral persistence in HAART. For example, the longevity of the latent reservoir may be partly attributable to continual replenishment by virus produced by active replication. It could be argued that, in the presence of HAART, there is not a complete life cycle within individual infected cells (that is, a cell gets infected but does not make particles) and that the infectious particles are being made by a chronically infected cell that is simply manufacturing virions. However, even in this scenario, conditions would exist for sequence evolution and for viral reservoir replenishment. Therefore, intensification"

ABSTRACT

Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted1, 2. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels3, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs4, 5. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.

Background: The stability of the CD4 T cell reservoir could be related to continuous replenishment from plasma residual HIV. Intensification with an entry inhibitor could help eliminate detectable levels of ongoing viral replication.

Results: Nine patients have been included. Median time of HIV diagnosis was 103 months (IQR 58 to 240 months), ART was administered for a median of 75 months (IQR 38 to 144 months), and the median BL CD4 count was 711 cells/mm3 (IQR 547 to 793). At BL, the reservoir could be quantified in 6 of 9 patients (mean 2.04 infectious units per million (IUPM)). At w12 of MVC intensification, all patients maintained VL <50 copies/mL (median CD4 count: 686 cells/mm3 (IQR 589 to 1,005 cells/mm3). A decrease in the latent reservoir was observed in 5 patients, while no decrease was found in one (mean 0.08 IUPM, P =0.048 compared to BL). Even though the BL RNA levels were at the assay limit for 8 of 9 patients, after w12 of intensification viral RNA level increased in 6 patients (range 0.5 to 9.2 copies/mL). Episomal 2-LTRs DNA was undetectable in the 9 patients at BL and turned detectable in 4 of them at w12. A significant decrease in the proportion of CD3+CD4+CD38+HLA-DR+ was observed at wk12 of intensification (median 2.9% (2.5 to 3.3) at BL vs 0.6% (0.4 to 2.4) after intensification, P =0.003. A trend of a decrease in CD3+CD8+CD38+HLA-DR+ was observed after intensification, median 5.4% (4.7 to 7.6) vs 2.3% (0.4 to 2.9), P =0.079.

Conclusions: In this preliminary analysis, intensification with MVC seems to accelerate the decay of the HIV latent reservoir. Unexpectedly, an increase in RV measured by SCA and episomal 2-LTRs DNA detection has been observed. A decrease in the activation of CD4 and CD8 cells was observed at wk12 of intensification.

Antiviral and Immunological Effects of Intensification of Suppressive ART with Maraviroc, a CCR5 Antagonist - see attached full poster report

Reported by Jules LevinCROI 2010

"As previously reported, levels of immune activation and CD4+ T cell depletion in the GALT persist when compared to PBMC. Thus far, we observe no statistically significant effect of intensification of ART with MVC on a variety of immunologic and virologic parameters in the GALT."

Methods: We enrolled adults infected with CCR5-tropic HIV-1 and treated with ART during acute, early infection. Subjects received ART for an average of 4 years prior to study entry and were randomized 2:1 to Arm A, 4 patients whose MVC was intensified for 24 weeks; or Arm B: whose NRTI was intensified for 12 weeks, 2 of whom were followed by cross-over to MVC for 12 weeks. Phlebotomy and flexible sigmoidoscopy with mucosal biopsies were performed at entry, weeks 12 and 24.

Results: Plasma HIV-1 RNA remained <50 copies/mL for all subjects throughout the study. Gastrointestinal biopsy RNA revealed <50 copies of HIV-1 NL43 gag for all participants at entry through week 24 (mean input of 1.5 x 106 copies of GAPDH/sample). At entry, no significant differences between arms A and B were measured for evaluated parameters. Immunohistochemistry revealed 5.36 ± 0.86 CD4+ T cells/unit area in the lamina propria at entry in Arm A. This did not increase significantly after 24 weeks. In contrast to Arm B, Arm A revealed non-significant decreases (P >0.10) in percentage of proliferating (MIB-1+) CD4+ T cells in the lamina propria between entry and week 12 (11.50% ± 2.50 vs 4.50% ± 1.94) and percentage of proliferating CD8+ T cells in the lamina propria between entry and week 12 (7.50% ± 5.20 vs 3.75% ± 1.11). No further decreases were noted after week 12. In Arm A, flow cytometry revealed significant differences (P <0.02) between the peripheral blood mononuclear cells (PBMC) and gut-associated lymphoid tissue (GALT) at entry in the CD4+CD8+ T cell ratio (1.47 ± 0.14 vs 0.91 ± 0.06) and percentage activated (CD38+) CD8+ T cells (2.61 ± 0.41 vs 17.61 ± 5.02). In Arms A and B, no statistically significant change (P >0.32) was noted in percentage of CD38+ or percentage of proliferating (Ki67+) CD4+ or CD8+ T cells in the GALT between entry, week 12 and week 24. Finally, in both arms, serum endotoxin activity was within the normal range at entry and did not significantly change after 24 weeks.

Conclusions: As previously reported, levels of immune activation and CD4+ T cell depletion in the GALT persist when compared to PBMC. Thus far, we observe no statistically significant effect of intensification of ART with MVC on a variety of immunologic and virologic parameters in the GALT.

ViiV Healthcare Calls for Initial Grant Proposals to the Positive Action for Children Fund

Ten Year Programme to Invest £50million in an effort to Improve the Health and Welfare of Women, Children and Families Affected by HIV

Today ViiV Healthcare announced the inaugural request for grant proposals (RFPs) through the Positive Action for Children Fund. Over the next ten years, ViiV Healthcare will invest £50 million in the Fund to support programmes focused on preventing HIV transmission from mother-to-child, as well as the health and well being of women, orphans and vulnerable children around the globe.

“Supporting the most vulnerable populations is core to ViiV Healthcare?s commitment to those affected by HIV and AIDS,” said Dominique Limet, CEO of ViiV Healthcare. “Community-based programmes have long been critical to successful HIV prevention, care and treatment. Through the Positive Action for Children Fund, we are assisting community initiatives tackling the problem of mother-to-child HIV transmission in systemic and sustainable ways.”

Following extensive consultations with some of the sector?s leading non-governmental organisations, practitioners and policy-makers in this field, the Fund will be focused on grants that pursue the four elements of the World Health Organization?s (WHO) strategic vision and comprehensive approach for addressing the mother-to-child transmission of HIV, under these four headings:

Johns Hopkins scientists have found that a safe and inexpensive antibiotic in use since the 1970s for treating acne effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and replicating.

The drug, minocycline, likely will improve on the current treatment regimens of HIV-infected patients if used in combination with a standard drug cocktail known as HAART (Highly Active Antiretroviral Therapy), according to research published now online and appearing in print April 15 in The Journal of Infectious Diseases. "The powerful advantage to using minocycline is that the virus appears less able to develop drug resistance because minocycline targets cellular pathways not viral proteins," says Janice Clements, Ph.D., Mary Wallace Stanton Professor of Faculty Affairs, vice dean for faculty, and professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.

"The big challenge clinicians deal with now in this country when treating HIV patients is keeping the virus locked in a dormant state," Clements adds. "While HAART is really effective in keeping down active replication, minocycline is another arm of defense against the virus."

Unlike the drugs used in HAART which target the virus, minocycline homes in on, and adjusts T cells, major immune system agents and targets of HIV infection. According to Clements, minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and progression toward full blown AIDS.

If taken daily for life, HAART usually can protect people from becoming ill, but it's not a cure. The HIV virus is kept at a low level but isn't ever entirely purged; it stays quietly hidden in some immune cells. If a person stops HAART or misses a dose, the virus can reactivate out of those immune cells and begin to spread.

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells. The Hopkins group connected the dots between that study with previous research of their own showing that minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T cell activation and proliferation.

"Since minocycline reduced T cell activation, you might think it would have impaired the immune systems in the macaques, which are very similar to humans, but we didn't see any deleterious effect," says Gregory Szeto, a graduate student in the Department of Cellular and Molecular Medicine working in the Retrovirus Laboratory at Hopkins. "This drug strikes a good balance and is ideal for HIV because it targets very specific aspects of immune activation."

The success with the animal model prompted the team to study in test tubes whether minocycline treatment affected latency in human T cells infected with HIV. Using cells from HIV-infected humans on HAART, the team isolated the "resting" immune cells and treated half of them with minocycline. Then they counted how many virus particles were reactivated, finding completely undetectable levels in the treated cells versus detectable levels in the untreated cells.

"Minocycline reduces the capability of the virus to emerge from resting infected T cells," Szeto explains. "It prevents the virus from escaping in the one in a million cells in which it lays dormant in a person on HAART, and since it prevents virus activation it should maintain the level of viral latency or even lower it. That's the goal: Sustaining a latent non-infectious state."

The team used molecular markers to discover that minocycline very selectively interrupts certain specific signaling pathways critical for T cell activation. However, the antibiotic doesn't completely obliterate T cells or diminish their ability to respond to other infections or diseases, which is crucial for individuals with HIV.

"HIV requires T cell activation for efficient replication and reactivation of latent virus," Clement says, "so our new understanding about minocyline's effects on a T cell could help us to find even more drugs that target its signaling pathways."

The research was supported by grants from the National Institutes of Health.

Authors of the paper, in addition to Clements and Szeto, are Angela K. Brice, Sheila A. Barber and Robert F. Siliciano, all of Johns Hopkins. Also, Hung-Chih Yang of National Taiwan University Hospital.

A new study has shown that HIV-infected patients are at a markedly increased risk for community acquired Methicillin-resistant Staphylococcus aureus (CA-MRSA) infections.

In the study, researchers at John H. Stroger, Jr. Hospital of Cook County and Rush University Medical Center found that the incidence of CA-MRSA in the Chicago area was six-fold higher among HIV-infected patients than it was among HIV-negative patients.

Using electronic data, the study authors retrospectively studied HIV-infected patients with CA-MRSA who received medical care during the period of 2000 to 2007 in the regional Cook County Health and Hospitals System. Researchers used patients' zip codes to examine where the cases were distributed geographically.

Overall incidence of CA-MRSA increased significantly for all populations in Cook County from the first period (2000- 2003) to the second period (2004-2007). The incidence increased four-fold from 61 cases to 253 cases per 100,000 HIV-negative patients and nearly four-fold from 411 cases to 1474 cases per 100,000 HIV-infected patients, respectively.

"HIV does not cause CA-MRSA, but our study shows an association between HIV and CA-MRSA. The next steps are to find out what is going on in the community to cause these infections," said study author Dr. Kyle Popovich, an infectious disease specialist at Rush University Medical Center.

"We believe the risk may be amplified by overlapping community-based social networks of high-risk patients," Popovich added.

The study has been published in the April 1 issue of the journal Clinical Infectious Diseases. (ANI)

Washington, DC: A novel stem cell therapy could in the future be used to treat HIV, say researchers.

Researchers are studying a new approach that arms the immune system with an intrinsic defence against HIV.

While speaking at the Society for General Microbiology's spring meeting in Edinburgh, Professor Ben Berkhout explained how this new approach could dramatically improve the quality of life and life expectancy for HIV sufferers in whom antiviral drugs are no longer effective.

In the absence of an effective vaccine, daily administration of anti-retroviral drugs is the most effective treatment for HIV. However, low patient compliance rates combined with the virus's ability to easily mutate has led to the emergence of drug-resistant strains that are difficult to treat.

Professor Berkhout from the University of Amsterdam is investigating a novel gene therapy that has long-lasting effects even after a single treatment. It involves delivering antiviral DNA to the patients' own immune cells that arms them against viral infection. "This therapy would offer an alternative for HIV-infected patients that can no longer be treated with regular antivirals," he suggested.

The therapy involves extracting and purifying blood stem cells from the patient's bone marrow. Antiviral DNA is transferred to the cells in the laboratory, after which the cells are re-injected into the body. The DNA encodes tiny molecules called small RNAs that are the mirror image of key viral genes used by HIV to cause disease. The small RNAs float around inside the immune cell until they encounter viral genes which they can stick to like Velcro(tm). This mechanism, called 'RNA interference' can block the production of key viral components from these genes.

Transferring the antiviral DNA to stem cells would help to restore a large part of the patient's immune system. "Stem cells are the continually dividing 'master copy' cells from which all other immune cells are derived. By engineering the stem cells, the antiviral DNA is inherited by all the immune cells that are born from it," explained Professor Berkhout.

Company Will Begin Non-Blinded Study in HIV Infected Individuals Who Started Drug Treatment During Their First Year of Infection

GeoVax Labs, Inc. (OTCBB: GOVX), a biotechnology company that creates, develops, and tests innovative HIV/AIDS vaccines, is now allowed by the FDA (US Food and Drug Administration) to begin a phase 1 clinical trial for GeoVax’s therapeutic vaccine, which is intended as a treatment for individuals infected with HIV (Human Immunodeficiency Virus). The company will begin a non-blinded study in HIV infected individuals who started drug treatment during their first year of infection. An unmet need exists in the market for a HIV therapeutic vaccine if it can reduce the need for expensive and poorly tolerated lifelong oral medications currently available to infected individuals.

There was big news from drug giant GlaxoSmithKline yesterday, which won European approval for Duodart and signed a deal with Isis to develop RNA therapeutics for rare diseases.

The UK drugmaker said it has entered into a strategic alliance with US firm Isis Pharmaceuticals, under which the latter?s antisense drug discovery platform will be used to identify and develop new therapeutics against targets for rare and serious diseases, including infectious diseases and some causing blindness.

Opposed to targeting a specific protein in a disease process, antisense therapies actually prevent protein synthesis by elimating the messenger RNA guiding its production. Isis? discovery platform has been constructed to develop specific therapies that bind to mRNA and thereby inhibit the production of disease-causing proteins.

“As a platform, the Isis antisense approach offers us an exciting opportunity to target certain severe diseases in a way that has not previously been possible,” said Patrick Vallance, Senior Vice-President and Head of Drug Discovery at GSK, explaining the group?s interest in the deal. “This new alliance will enhance our discovery platform in this promising research area,” he added.

Under the terms of the deal, which covers up to six programs, Isis stands to receive an upfront cash pile of $35 million, and is also eligible an average of up to $20 million in milestones per program up to the Phase II proof-of-concept stage, at which point GSK can license the compounds if it chooses to and take over all further development and commercialisation.

The deal is certainly huge for Isis, as the group could gain total payments of nearly $1.5 billion if all six programmes are successfully developed in one or more indication, as well as double-digit royalties on sales any product that makes it to market.

Duodart green lightMeanwhile, GSK also announced yesterday that European regulators have waved through Duodart - a fixed dose combination of dutasteride and tamsulosin - for the treatment of moderate-to-severe symptoms of Benign Prostatic Hyperplasia (BPH) and reduction in the risk of acute urinary retention (AUR) and surgery in patients with moderate-to-severe symptoms.

The drug?s approval came on the back of results from the CombAT, which study showed that the combination of dutasteride (marketed as Avodart) and tamsulosin offers patients with moderate-to-severe symptoms of BPH a “significantly superior and sustained symptom improvement” compared with tamsulosin, the most frequently prescribed medication, as well less risk of complications associated with BPH, including a 66% reduction in the risk of AUR and surgery.

According to Eddie Gray, President, Pharmaceuticals Europe at GSK, the firm developed the new fixed-dose combination medicine “to provide patients and physicians a convenient, once-daily treatment, which reduces the impact of the bothersome symptoms of this common condition, and the risk of potential complications and related surgery,” factors which can “create uncertainty and anxiety for many men and may also lead to additional unplanned costs for healthcare providers”.Inline Attachment Follows: 3341017962.txt

April 1 (Bloomberg) -- Gilead Sciences Inc. may learn this year whether its drugs for treating HIV can also stop people from catching the virus in the first place.

The approach may help curb the AIDS pandemic in poor countries and bring Gilead $1 billion a year in additional U.S. sales, said Josh Schimmer, an analyst at Leerink Swann & Co. in Boston. Most investors aren’t alert to the potential benefit, he said. Researchers are compiling the first data from 10 trials involving more than 20,000 people, and initial results may be available in July.

“This could be very meaningful for Gilead,” Schimmer said in a telephone interview. “You’re potentially treating 50 patients to prevent one. Commercially that’s very attractive. I don’t hear anybody talking about this, and I think all of us should be more aware.”

If the strategy works, the pills from Foster City, California-based Gilead may promise the world a powerful tool for fighting AIDS, the deadliest infectious disease, after scientists’ failure so far to develop an effective vaccine or virus-killing gel.

Skeptics say the approach, called pre-exposure prophylaxis, or PrEP, may be too costly and impractical in sub-Saharan Africa, where 22 million people are infected with HIV -- putting millions of others at risk -- and per-capita income is $951 a year.

Side effects may also undermine the plan. While doctors regard Gilead’s drugs as relatively safe, nobody knows what the medicines do in people who are taking them for a disease they don’t have, or how eager these patients will be to put up with the diarrhea, dizziness and depression the pills may cause.

‘High Tolerance’

“People have a high tolerance for side effects if it’s saving their life,” said Mitchell Warren, executive director of the New York-based AIDS Vaccine Advocacy Coalition, a nonprofit advocacy group. “It may be harder for healthy people to accept the side effects that come with prevention.”

The trials involve giving Gilead’s Viread and Truvada, the world’s top-selling AIDS medicine, to HIV-negative people from groups most at risk of contracting the virus, such as gay men who have unsafe sex and drug users who share hypodermic needles. Results from five of the studies may be available this year, according to the researchers running them.

One trial, scheduled to report data at an AIDS conference in July, is testing Viread as a vaginal gel in women who apply it before sex. Another is measuring the preventive effect of a daily Truvada pill among 3,000 gay men in six nations.

A further three studies coordinated by the U.S. Centers for Disease Control and Prevention, based in Atlanta, are testing PrEP among gay men in the U.S., drug users in Thailand and heterosexuals in Botswana. Gilead, while donating drugs and technical advice, isn’t running the trials, the company said.

Behavior Monitored

The studies are also designed to measure whether people receiving the drugs become riskier in their behavior, in the belief they’re protected against the virus. Participants receive testing, condoms and counseling on ways to avoid infection.

If the tests are successful, PrEP distribution programs could begin in developing countries in 2012, said Bill Gates, co-founder of Microsoft Corp. and the Bill & Melinda Gates Foundation, both of Seattle. He spoke to the U.S. Senate Foreign Relations Committee about global health priorities on March 10. The Gates Foundation is sponsoring three PrEP trials.

The CDC would try to issue guidelines on the use of PrEP to health-care providers within six months of successful test results, said Jennifer Horvath, an agency spokeswoman, in an e- mail.

First Defense

“PrEP is the next big thing,” said Warren of the AIDS Vaccine Advocacy Coalition, in a telephone interview. “We have a level of biological plausibility and early data in animal studies that is stronger than anything we have seen in the other approaches.”

Gilead had revenue of $7.01 billion last year, including sales of $5.54 billion from its top three AIDS drugs -- Truvada, Atripla and Viread -- which are taken by 85 percent of HIV patients in the U.S. as a first defense against the virus.

Gilead rose 17 cents, or less than a percent, to $45.64 at 4 p.m. New York time in Nasdaq Stock Market composite trading. The shares have increased 1 percent in 12 months. Investors aren’t sure what to make of the PrEP trials, said Jason Kantor, an analyst at RBC Capital Markets in San Francisco.

“This is not currently a focus for investors, and I have nothing in my estimates for this,” Kantor said an e-mail. “Positive data, if compelling, could be a small incremental benefit in the developed countries.”

Implications Unknown

PrEP sales in the U.S. may range from “negligible” to as much as $1 billion annually, depending on the effectiveness of the drugs and how much patients and public-health agencies are willing to pay for prevention, Leerink’s Schimmer said.

“It’s going to depend upon the data,” Rooney said in a phone interview. “And it’s going to depend upon how the public- health officials evaluate the data and translate that into recommendations for clinical practice.”

Gilead will decide whether to seek regulatory approval of its drugs for prevention once results of the trials are known, Rooney said.

Doctors would be able to prescribe the medicines for prevention without the approval. A study published last year in the Journal of Acquired Immune Deficiency Syndromes found that among 277 gay men in Boston, one had used PrEP and 74 percent said they would use it if it were available.

Breast Milk

Drugs made by GlaxoSmithKline Plc of London and Boehringer Ingelheim GmbH of Ingelheim, Germany, are already used to prevent infected mothers from passing the virus to their babies in the womb or through breast milk. Glaxo’s Combivir is prescribed to prevent infections in men who take it after unprotected sex with an HIV-positive partner.

Those medicines show that using treatments as prevention can work, said Dawn Smith, a CDC researcher who is devising the agency’s plans to implement PrEP if the clinical trials succeed.

“I’m very hopeful that this approach will help to reduce HIV infection rates,” Smith said in a telephone interview. “But I’m enough of a scientist to be skeptical as well, and to want to see the trial results before I call myself a believer.”

Gilead’s drugs subdue HIV in infected patients by blocking an enzyme the virus needs to hijack cells in order to reproduce. Taken preemptively, the pills may prevent HIV from gaining a foothold when it first enters the body.

‘Good Reason’

A study presented at the Conference on Retroviruses & Opportunistic Infections, in Montreal last year, found Truvada cut the risk of infection almost 16-fold in monkeys. A 2007 trial of PrEP among 936 women in Africa concluded that a daily Viread pill cut the risk of infection by 65 percent, though the researchers said the trial didn’t produce enough data to prove conclusively that PrEP worked.

“From a scientific standpoint, there really is a good reason to believe that if properly done, it will work,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, based in Bethesda, Maryland, said at this year’s retroviruses conference, held in San Francisco in February.

There may be less reason to think PrEP is feasible, Fauci said.

“If we can’t get 70 percent of the people who are infected in low- and middle-income countries on therapy, how are we going to get people who aren’t even infected on therapy?” Fauci said.

If it does work, PrEP won’t come cheap. Giving Truvada to the 100,000 most at-risk gay men in the U.S. would cost more than $1 billion a year, the CDC said on its Web site. That sum covers only the cost of the pills, and doesn’t include marketing, HIV testing, and doctors’ visits.

‘Deep Down Horror’

Identifying people who are at sufficient risk of contracting HIV to receive PrEP will most likely be too difficult in Africa, where everyone who is sexually active is at risk, said Francois Venter, president of the Southern African HIV Clinicians Society, a professional group based in Johannesburg.

“Deep down I have this horror that we’ll have an effective intervention very few people are going to use,” Venter said in a telephone interview. “In America and Europe it’s probably going to be one of several interventions which are going to work. I worry that there hasn’t been enough focus on who’s going to take these drugs in my environment.”

To justify the expense of handing out drugs to people who don’t have HIV, the trials need to show that PrEP lowers the chances of infection by at least half, said Francoise Barre- Sinoussi, a French researcher who shared the 2008 Nobel Prize in medicine after helping to discover that HIV causes AIDS.

‘Little Bit Concerned’

“We will have encouraging information from those trials,” Barre-Sinoussi said in an interview in Singapore. “I’m just a little bit concerned about how to apply it at large scale.”

About 33 million people live with HIV, according to UNAIDS, the coalition of United Nations agencies formed to fight HIV. In 2008, 2.7 million people were newly infected with the virus and 2 million died from AIDS-related complications. Africa has 7 in every 10 of the world’s cases.

Assuming PrEP could prevent 50 percent of infections, it would almost cut in half the lifetime risk of catching HIV among high-risk gay men in the U.S., and almost triple the lifetime treatment costs, according to a computer simulation published in the journal Clinical Infectious Diseases in March 2009.

PrEP is “unlikely to confer sufficient benefits to justify the current costs” of Truvada in the U.S., researchers from Yale University in New Haven, Connecticut, and Harvard Medical School in Boston wrote in the study. The model assumed a drug cost of $753 a month for each patient.

Drug Costs

Gilead sells a month’s supply of Viread to U.S. wholesalers for about $643. A month of Truvada costs about $930, said Cara Miller, a company spokeswoman, in an e-mail. The company charges people in poor countries about $17 a month for Viread and $26 for Truvada, she said. About 700,000 people worldwide take brand-name or generic versions of Gilead’s AIDS drugs, Miller said.

When the first AIDS drugs were approved in the U.S. in 1987, critics said they weren’t affordable in poor nations, the CDC’s Smith said. Now, about 40 percent of the patients who need them are getting the medicines, according to UNAIDS. PrEP may also prove more adoptable than its critics think, Smith said.

“If it’s highly efficacious, and if countries and UNAIDS and WHO and other public health agencies believe that it has a role to play in reducing new HIV infections, then we will find a way to make it available,” Smith said.

A 42-year-old HIV patient with leukemia continues to show no signs of HIV in his blood, two years after a stem cell transplant from a donor with a gene mutation that confers natural resistance to the virus that causes AIDS.

The stunning findings were published Wednesday in The New England Journal of Medicine, according to CNN, but doctors caution that the stem cell treatment is too dangerous to be of routine use to most people infected with HIV.

In the study, reported CNN, “the team deliberately chose a compatible donor who has a naturally occurring gene mutation that confers resistance to HIV. The mutation cripples a receptor known as CCR5, which is normally found on the surface of T cells, the type of immune system cells attacked by HIV.

“The mutation is known as CCR5 delta32 and is found in 1 percent to 3 percent of white populations of European descent.

“HIV uses the CCR5 as a co-receptor (in addition to CD4 receptors) to latch on to and ultimately destroy immune system cells. Since the virus can't gain a foothold on cells that lack CCR5, people who have the mutation have natural protection. (There are other, less common HIV strains that use different co-receptors.)

“People who inherit one copy of CCR5 delta32 take longer to get sick or develop AIDS if infected with HIV. People with two copies (one from each parent) may not become infected at all. The stem cell donor had two copies.”

Doctors say that while the risky stem cell transplant option should not be routinely exercised, the findings point the way toward development of potentially safer CCR5-disabling gene therapies or treatments that can be injected into the body.

At the meeting just completed this year there were a bunch of new study results presented on the use of Pegasys for HBV with links to study results below. As well, there were updates with 3-year followup on tenofovir for HBV, and new entecavir studies including in patients with hepatic decompensation, and several studies from BMS reporting on 3 new HCV drugs they are developing: the NS5A inhibitor BMS790052, the protease inhibitor BMS6 50032, and their new lambda interferon which in early studies shows less side effects than standard peginterferon with similar antiviral activity. Jules Levin

APASL: Sustained Immune Control 1 Year Post-Treatment with Peginterferon Alfa-2a [40KD] (PEGASYS) is Durable up to 5 Years Post-Treatment and is Associated with a High Rate of HBsAg Clearance in HBeAg-Negative Chronic Hepatitis B - (03/31/10)

SCYNEXIS Announces Acceptance of Abstracts Related to its Hepatitis C Clinical Candidate, SCY-635, for Presentation at 45th Annual Meeting of the European Association for the Study of the Liver

RESEARCH TRIANGLE PARK, N.C. --(Business Wire)-- Drug discovery company, SCYNEXIS, Inc. today announced that multiple abstracts related to the Company's cyclophilin inhibitor, SCY-635, were accepted for presentation at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria, April 14-18, 2010. SCY-635, a cyclophilin inhibitor, represents a new class of drugs for the treatment of hepatitis C virus (HCV) infection and is the first candidate from a broad platform of proprietary cyclophilin inhibitors developed by SCYNEXIS. Full abstracts can be viewed at the EASL website at www.easl.eu.

we found high levels of mistrust about HIV treatment and the governments' role in the HIV epidemic. Adherence rates were generally low.....HIV conspiracies cannot be dismissed as rare or extreme. Such beliefs can ultimately contribute to decreased survival time

The present study was conducted among African American men with HIV in the Los Angeles, CA, area. We recruited 214 African American men with HIV on antiretroviral treatment using fliers disseminated and posted by staff at 3 HIV social service agencies and an HIV medical clinic........Almost two-thirds (64%) agreed with at least 1 HIV conspiracy belief; about half (48%) agreed with 2 or more. Forty-four percent believed that HIV is manmade, 35% thought that AIDS was created in a government laboratory, and a third endorsed the genocidal belief related to a cure being withheld (Table 1). Conspiracy beliefs about medications were also substantially endorsed, with 22% believing that people who take the new HIV medications are human guinea pigs for the government and 17% believing that the medications are poison. Participants who screened positive for depression and who had higher incomes were more likely to endorse at least 1 conspiracy belief.....On average, participants took only 68% of the prescribed doses of their HIV antiretroviral medications during the month between the baseline and follow-up assessments (Table 2). Only 22% of participants demonstrated an optimal level of adherence (ie, ≥95% of doses)

Conspiracy Beliefs About HIV Are Related to Antiretroviral Treatment Nonadherence Among African American Men With HIV

Background: Medical mistrust is prevalent among African Americans and may influence health care behaviors such as treatment adherence. We examined whether a specific form of medical mistrust-HIV conspiracy beliefs (eg, HIV is genocide against African Americans)-was associated with antiretroviral treatment nonadherence among African American men with HIV.

From the *University College Medical School, London, United Kingdom; †Royal Free Hampstead NHS Trust, London, United Kingdom; ‡Medical Research Council Clinical Trials Unit, London, United Kingdom; and §Chelsea and Westminster Hospital, London, United Kingdom.

Abstract

Objective: The study aim was to determine how resistance testing influences outcome of first-line highly active antiretroviral therapy (HAART) in routine practice in the United Kingdom.

Methods: The prevalence of transmitted drug resistance and the genotypic sensitivity score (GSS) of first-line HAART regimens were determined using data from the UK Collaborative HIV Cohort (CHIC) Study. Factors associated with starting a regimen with a reduced GSS and subsequent virological responses were analyzed by logistic and Cox regression.

Overall, 21.0% (232,700; 95% CI = 221,200-244,200) of estimated prevalent HIV cases were undiagnosed.....The highest percentage of undiagnosed HIV (26.7%) was among men with a transmission category of high-risk heterosexual contact (HRHC), defined as reporting heterosexual contact specifically with a person known to have, or to be at high risk for, HIV infection (eg, an injection drug user). The second highest percentage of undiagnosed HIV was among MSM (23.5%).

Undiagnosed HIV Prevalence Among Adults and Adolescents in the United States at the End of 2006

From the Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA.

Abstract

Objectives: To describe adults/adolescents (age 13 years and older) living with undiagnosed HIV infection in the United States at the end of 2006.

Methods: HIV prevalence and percentage undiagnosed were estimated from cumulative HIV incidence using an extended back-calculation model (using both HIV and AIDS data, the time of first diagnosis with HIV, and disease severity at diagnosis) and estimated cumulative deaths.

Spending on prescription drugs topped $300 billion in the U.S. last year, rising 5.1% despite the economic downturn, according to IMS Health. But the rate of growth was at the low end of historical levels, reinforcing the difficulties brand-name drug makers face relying on the U.S. market to increase revenue.

The number of prescriptions dispensed in the U.S. also edged higher last year, increasing 2.1% to 3.9 billion, IMS Health reported Thursday. IMS Health collects data from drug makers, pharmacies and other sources and advises companies on health-care trends.

The results underscore the "resilience" of prescription-drug demand in the face of a down economy, said Murray Aitken, a senior vice president at IMS Health. In 2008, the spending rose just 1.8%, only the third time since 1957 the rate of growth was below 5%.

Investors have traditionally viewed pharmaceutical stocks as good options during down economies, although some companies, such as Merck & Co., said the recent recession was damping sales.

Still, the data pointed to concerns for branded drug makers. The number of prescriptions dispensed for generic drugs rose 5.9% last year, but those for branded drugs declined 7.6%. Of all prescriptions dispensed, 75% were for generics last year, up from 57% five years earlier.

Partly due to the rising use of those generics, prescription-drug spending managed to increase overall for the year to $300.3 billion, Mr. Aitken said. Drug makers and retailers also encouraged prescription-drug use by offering patients discounts on co-pays and other incentives. Slightly higher prices for certain brand-name treatments also contributed to higher revenue.

IMS Health said it couldn't specify how much the prices for brand-name drugs increased.

Sales of brand-name drugs are expected to keep rising at relatively low rates in the mid-single digits, Mr. Aitken said. Making matters difficult for brand-name drug makers, several of their top-selling medicines, including Pfizer Inc.'s popular Lipitor, are scheduled to lose patent protection over the next few years.

One sign of the problems ahead for branded drug companies was in the results for cholesterol-fighting drugs. They continued to be the largest class of prescription medicines by prescription volume. But they dropped to third place from second in terms of overall sales, due to rising use of generic versions.

Antipsychotic medicines were the top-selling class of drugs in the U.S. last year, with sales of $14.6 billion. Proton-pump inhibitors were second with sales of $13.6 billion, IMS Health said.

In an ongoing phase I/II trial, 17 HIV-1-infected subjects who were fully suppressed on ART received over a period up to 14 weeks 3 or 6 infusions each of 10 to the 10th autologous CD4 T cells transduced with a lentiviral vector encoding a 937 nucleotide HIV env antisense construct (VRX496) and expanded ex vivo. To evaluate the effects this therapy had on viral set points and CD4 counts, eligible subjects underwent scheduled treatment interruption (STI) six weeks after the last infusion.

Every year, Canada’s centralised review body, the Common Drug Review (CDR), rejects the majority of new drugs put forward for coverage by the nation’s publicly-funded drug plans, largely because their makers have failed to address problems raised by other health technology assessment agencies (HTA) such as NICE, a leading expert says.

Moreover, for almost all products which the CDR does recommend, the decision comes with restrictions, Neil Palmer, president of pricing and reimbursement consultancy PDCI Market Access, told a recent conference in London.

The drug plans run by Canada’s 10 provinces and three territories account for 45% of the nation’s total spending on prescription drugs, and their share reached an estimated C$11.4 billion in 2009, according to the Canadian Institute for Health Information (CIHI). The CDR advises the plans (apart from Quebec’s) as to which products they should cover, based on clinical and pharmacoeconomic reviews but not budget impact - this is assessed by each individual plan.

The provinces have been slow to implement positive CDR recommendations largely because of budget concerns, but they have begun addressing these through negotiating various types of agreements with manufacturers, and in some provinces such deals are now a requirement for listing, Mr Palmer told the conference, which was organised by Health Network Communications.

For example, Ontario’s Transparent Drug System for Patients Act of 2006 created an “executive officer” position that could negotiate and implement agreements with manufacturers.

A number of studies have concluded that the CDR is “more restrictive” than other HTA agencies, said Mr Palmer. For example a recent comparison of the decisions taken for 64 drugs by the CDR and the Scottish Medicines Consortium (CMR) found that the Canadian agency recommended just 1.6% of the products for listing, while the SMC recommended 34.4%. The percentages for “list with restrictions” and “do not list” were 51.6% and 46.9% respectively for the CDR, compared with 43.8% and 21.9% for the Scottish agency.

Analysis suggests that the CDR “is unconvinced” that new products offer incremental value when older, less expensive alternatives are available. And, while Canada has no official incremental cost-effectiveness ratio threshold, the probability of rejection increases speedily once it goes over C$50,000 per Quality-Adjusted Life Year (QALY) and is almost certain above C$70,000 per QALY, said Mr Palmer.

- Health Canada takes an average of 388 days to approve a new drug, after which the provinces take a further 316 days to decide whether to include it on their drug programmes. Moreover, by the end of 2009, only 23% of new drugs approved by Health Canada in 2004 had been approved for either full or partial reimbursement under provincial drug plans, according to a report published last month by Canadian free-market think tank The Fraser Institute.

“In the end, the provinces usually choose not to cover these drugs, leaving the one-third of Canadians who rely on provincial drug plans without access to most new medicines,” said report co-author Mark Rovere, a senior policy analyst at the Institute.

One solution to this problem, he suggests, could be for Canada to take better advantage of the regulatory knowledge and capacity of other jurisdictions, rather than attempting to duplicate the drug approval process used by the US Food and Drug Administration (FDA). By entering into agreements of mutual recognition with other countries, new medications already approved in those countries could be introduced into the Canadian market far more rapidly, he proposes.

Moreover, the report says, the most economically rational way to improve access to new medicines without increasing the burden on taxpayers would be to replace the publicly-funded drug programmes with means-tested, subsidised access to a “a properly regulated, competitive private-sector insurance market.”

“The best policy choice for improving access to the newest prescription drugs is to allow the private insurance market to compete through price and service,” says Mr Rovere.

Pittsburgh, PA - The largest study so far to examine the use of antioxidant doses of vitamins C and E to prevent the complications of pregnancy-associated hypertension, including preeclampsia, has found no benefit of this approach [1].

"The bottom line was that within the groups of women we studied, using the same doses of vitamins C and E that were used in all other studies, the groups are virtually superimposable—as far as every primary and secondary outcome, they are almost indistinguishable; there is no evidence of any benefit," lead author Dr James Roberts (University of Pittsburgh, PA) told heartwire. He and his coauthors report their findings in the April 8, 2010 issue of the New England Journal of Medicine.

"Women should continue to take prenatal supplements, which have these vitamins in them but at a fraction of the dose," he continued. "But there is no justification for recommending these medications to try to prevent preeclampsia or to try to prevent the complications of preeclampsia at this time," he commented.

No benefit of vitamins on primary outcome or any secondary end points

Roberts explained that the idea that oxidative stress is involved in the development of preeclampsia gained ground during the late 1990s, when a small study involving high-risk women showed a 60% reduction in diagnosis of preeclampsia with supplementation with antioxidant doses of vitamins C and E compared with placebo.

This prompted several other groups to examine this issue, but none were able to replicate the original positive findings.

Roberts said this new study was unique among trials in this field in that they decided the end point would not be a diagnosis of preeclampsia but rather whether the vitamins had any effect on new-onset pregnancy-associated hypertension. This meant they could assess whether the therapy would prevent serious complications rather than merely modify diagnostic findings, he explained.

The multicenter, randomized, double-blind trial conducted between July 2003 and February 2009 involved nulliparous women at low risk for preeclampsia who were randomly assigned to 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo between the ninth and 16th weeks of pregnancy. Therapy in this study was initiated at an earlier stage of gestation than in any of the previous trials, Roberts noted.

Outcome data were available for 9969 women; there was no significant difference between the vitamin and placebo groups in the rates of the primary outcome (6.1% and 5.7%, respectively; relative risk 1.07) or in the rates of preeclampsia (7.2% and 6.7%; relative risk 1.07), a major secondary outcome.

There was also no evidence of a benefit with vitamin therapy with respect to any of the other prespecified secondary outcomes, the researchers note.

Vitamins associated with slight increase in BP, but not low birth weight

On a positive note, there was no evidence of an excess of low-birth-weight babies among those taking the vitamin supplements in this study, said Roberts, something that was found in a previous trial, the UK Vitamins in Preeclampsia (VIP) study.

But researchers did find a slight increase in blood pressure in the women who took vitamins, a finding that was also observed in the VIP study and a similar Australian trial, said Roberts.

"The expectation [was a lowering of BP], but in all three studies not only was there not a reduction, there was actually an excess of higher blood pressure, but not of preeclampsia. So there is something to suggest that either vitamin C or E might have an effect on BP to increase it slightly, but other than that we had no adverse outcomes in our study," Roberts noted.

Vitamins C and E not the answer, but oxidative stress may still play a role

"It's definitely established that the drugs we gave at the doses we gave, when we gave them, did not reduce any of the problems in either high- or low-risk patients when you put all the studies together," Roberts said.

He also noted that these vitamins didn't work in cardiovascular-disease prevention, either: "The cardiovascular literature suggests C and E are not the answer if antioxidants are valuable." However, he still believes that oxidative stress somehow plays a role in the development of preeclampsia: "People haven't completely given up on the fact that oxidative stress—which is what we were treating with those vitamins—is part of the disease, and we will continue to look for a group that might have benefit."

There are also a couple of trials starting in the UK looking at other antioxidants—selenium, for example, he notes. "Beyond oxidative stress, inflammation is an interesting area, and there is some suggestion that statins may be useful, and there may be a small trial going on."

Second, smaller study replicates findings

A second, smaller study has also found that antioxidant supplementation with the same doses of vitamins C and E did not reduce the rate of preeclampsia or gestational hypertension in almost 2500 women [2]. The study was stopped early, partly because of an increased risk of fetal loss or perinatal death in those treated with the vitamins as opposed to the women who received placebo, although the difference between the two was not statistically significant, say Dr Hairong Xu (University of Montreal, QC) and colleagues in their paper in the March 2010 issue of the American Journal of Obstetrics & Gynecology.

"Vitamin-C and -E supplementation at the above doses cannot be recommended for pregnant women to prevent adverse pregnancy outcomes including preeclampsia," they conclude.

Financial and other disclosures provided by the authors of the New England Journal of Medicine paper are available with the full text of this article at NEJM.org. No disclosures are listed for the paper in the American Journal of Obstetrics & Gynecology.

Levels of darunavir and raltegravir, both mainly metabolized by the liver, were higher in HIV-infected people with moderate to severe liver disease than in a comparison group of HIV-positive people without liver problems [1]. Darunavir troughs were substantially higher in people with cirrhosis than in people with more moderate liver impairment.

This small case-control study involved 5 Caucasian men coinfected with HIV and hepatitis C virus (HCV) who started a regimen containing both the integrase inhibitor raltegravir and the protease inhibitor darunavir. Researchers at Rome's INMI Lazzaro Spallanzani Infectious Diseases Department collected blood samples from these 5 men 14 and 30 days after their started their raltegravir/darunavir-based regimen. They compared raltegravir and darunavir levels in these men with levels in 24 people without HCV who were taking these two drugs for HIV.

The 5 HIV/HCV-coinfected men averaged 48 years in age (+/- 5 standard deviation). They had been infected with HIV for an average 16 years and had an average lowest-ever CD4 count of 58 and an average body mass index of 23 kg/m(2) (+/- 1.3). Along with raltegravir and darunavir, 2 men were taking a second protease inhibitor, 2 were taking two nucleosides, and 1 was taking a nonnucleoside. Ultrasonography indicated that 3 men had cirrhosis (Child Pugh stage B) and 2 had chronic active HCV-related hepatitis.

Raltegravir trough concentrations averaged 637 ng/mL in the men with liver impairment versus 221 ng/mL in the HCV-negative controls. The 3 men with cirrhosis had a raltegravir trough of 665 ng/mL, compared with 581 ng/mL in the 2 HIV/HCV-coinfected men without cirrhosis.

Darunavir troughs in coinfected men averaged 8519 ng/mL, compared with 3236 ng/mL in the control group. Darunavir troughs averaged 9820 ng/mL in the 3 men with cirrhosis versus 2016 ng/mL in the 2 coinfected men without cirrhosis.

Virologic and immunologic results were similar in the 3 men with cirrhosis and the 2 without cirrhosis, and antiretroviral safety over the course of this study did not differ between these two groups. One of the men with cirrhosis died 1 month after starting the raltegravir/darunavir regimen because of acute liver and kidney disease.

On the basis of this small case-control comparison, the investigators suggest "special caution in the use of raltegravir, and especially of darunavir, in patients with moderate to severe liver impairment because of the risk of additive toxicity."

US prescribing information already advises clinicians to "monitor liver function before and during therapy [with darunavir/ritonavir], especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases." For raltegravir, US prescribing information cites "no clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and healthy subjects" but cautions that "the effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied."

Among Canadian women with an undetectable viral load, minimum concentrations (Cmins) of four antiretrovirals were 22% higher than in a mostly male general-population comparison group [1]. Unboosted or boosted atazanavir maximum concentrations (Cmax) were substantially lower in women than in the general population, and nevirapine Cmins were much higher. Overall, Cmins were highly variable within and between antiretrovirals.

Previous research has found higher antiretroviral concentrations in women than in men, but research on this issue is limited. To get a better fix on concentrations of four major antiretrovirals in women with an undetectable viral load, Charles la Porte and colleagues at 14 Canadian sites conducted a cross-sectional study of 83 women taking their first regimen. The researchers collected timed blood samples weekly for 3 weeks. They compared median Cmax and Cmin in individual women with published average Cmax and Cmin from a general population group consisting mostly of men.

The investigators excluded women with poor antiretroviral adherence, pregnant or breastfeeding women, those not taking standard doses, and those with end-stage organ disease, other significant non-HIV disease, or malignancy requiring chemotherapy.

The 83 women had a median age of 42 years (interquartile range [IQR] 36 to 48) and a median current CD4 count of 490 (IQR 380 to 640). Median weight stood at 67.3 kg (IQR 60.3 to 81.7) and median body mass index at 25.5 kg/m(2) (IQR 22.3 to 31.0). Women had taken their first antiretroviral regimen for a median of 3.8 years (IQR 1.8 to 7..

Overall median antiretroviral Cmin was 22% higher in these women than in the general population group (ratio 1.22, IQR 0.72 to 1.93). That difference was driven by lopinavir (ratio 1.22, IQR 0.79 to 1.81) and nevirapine (ratio 1.62, IQR 0.91 to 2.32). But the study disclosed no significant predictors of high Cmin.

Median Cmax was 14% lower in the women than in the general population (ratio 0.86, IQR 0.59 to 1.25), and that difference could be traced primarily to unboosted atazanavir (ratio 0.53, IQR 0.28 to 0.94), boosted atazanavir (ratio 0.67, IQR 0.54 to 0.85), and efavirenz (ratio 0.79, IQR 0.57 to 1.27).

Percentages of women with a Cmin more than 1.5 times above the population average were 20.0% for unboosted atazanavir, 27.8% for boosted atazanavir, 30.0% for lopinavir, 37.5% for efavirenz, and 52.6% for nevirapine. Percentages of women with a Cmax more than 1.5 times above the population average were 0% for boosted or unboosted atazanavir, 25.0% for lopinavir, 25.0% for efavirenz, and 15.8% for nevirapine.

Within-patient variability for Cmin and Cmax were greatest for unboosted atazanavir (52.3 and 63.9) and lowest for efavirenz (17.7 and 15.5) and nevirapine (17.5 and 15.7)

Raltegravir Is a Potent Inhibitor of XMRV, a Virus Implicated in Prostate Cancer and Chronic Fatigue Syndrome - (04/03/10)

PLoS one, April 1 2010

"XMRV nucleic acid or proteins are found in 27% of prostate cancers and in 68% of chronic fatigue syndrome patients, and in less than 4-6% of normal controls, suggesting an association between the virus and human disease....The discovery of effective antiretroviral agents against XMRV would allow for rational design of clinical trials to prevent progression of prostate cancer or to treat CFS.....We report here for the first time that the integrase inhibitor, raltegravir (RAL), is extremely potent and selective against XMRV, when used at low submicromolar concentrations in both cell culture systems. Another IN inhibitor, L-000870812, and two NRTIs, ZDV and tenofovir disoproxil fumarate (TDF), also inhibit XMRV replication, but at higher concentrations. When combined, these compounds display synergistic effects, suggesting combined modalities to treat XMRV infection, thus delaying or preventing the selection of resistant viruses."

"Twenty-eight out of 106 (26.4%) co-screened patients harboured a R5-tropic virus and were thus enrolled in the study....All had been previously exposed to NRTIs, NNRTIs and at least three protease inhibitors, including lopinavir/ritonavir [28/28 (100%)], tipranavir/ritonavir [4/28 (14%)], and darunavir/ritonavir [10/28 (36%)]. Eleven (39%) patients had been previously treated with enfuvirtide......At week 48, all patients had an HIV-RNA load below 400 copies/ml (P < 0.0001) and 26/28 (93%) had less than 50 copies HIV-RNA/ml (P < 0.0001)......At week 48, the median increase in CD4+ cell count was 267 (136-355) cells/µl (Fig. 1b). The proportion of patients with CD4+ cell counts below 200 cells/µl was 36% (10/28) at baseline, and 7% (2/28) at week 48 (P = 0.0082)......In our study, the combination of raltegravir and maraviroc, and etravirine led to an unexpected rate of virological success, with a rapid and robust CD4+ cell recovery, despite a high pill burden regimen and potentially negative drug-drug interactions......we observed an improvement of lipid profile.In conclusion, our results suggest that a protease inhibitor and NRTI-sparing regimen of raltegravir and maraviroc, and etravirine is potent and well tolerated. Although long-term toxicity needs to be accurately evaluated, this regimen may represent a powerful option to regain full viral control and robust CD4+ cell recovery in patients with extensive drug resistance and R5-tropic HIV."

Using administrative data from more than 67,000 Henry Ford Health System patients, physicians found that over the period 1997-2008, 0.6 percent patients with hepatitis C infection developed kidney cancer whereas only 0.3 percent patients without the disease developed kidney cancer.

“These results add to growing literature that shows that the hepatitis C virus causes disease that extends beyond the liver, and in fact most of our HCV-infected kidney cancer patients had only minimal liver damage,” says Stuart C. Gordon, M.D., director of Hepatology at Henry Ford Hospital and lead author of the study.

The study was published in this month’s Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research. (ANI)

There have been publications in journals, lots of studies and discussion about inflammation, aging & chronic diseases in HIV-negatives for years, so this is NOT a new subject outside of HIV. It has been widely recognized that inflammation is associated with chronic viral diseases, HIV-negative individuals with chronic viral diseases have ongoing inflammation which is associated with a dysregulated immune system. So observing this in HIV is no surprise and should have been expected although when these observatios started emerging in HIV at CROI, the annual HIV conference, several years ago it appeared to take the field by surprise and NO ONE was discussing this or paying much attention. At first large cohort studies in Europe and small studies in the USA reported premature onset of comorbidities, heart disease/cancers/bone disease/cognitive impairment/kidney function decline etc. At the same time I started reporting about these developments and in particular early onset of bone disease and osteopenia/otseoporosis in a significant percent of patients. Many researchers and officials gave me pushback that bone disease may not translate into increased fractures in HIV, and I had to laugh. Of course at this year's CROI several studies reported increased fracture rates in HIV and that HIV+ men face a unique concern regarding bone disease unlike among HIV-negative individuals where women present a more unique problem. And premature death was also found and associated with patients developing these comorbidities. Make no mistake about it, despite tremendous benefits to HAART an HIV-infected person still has a dysfunctional and weakened immune system, this is at the core of the aging and inflammation problems. Starting 2 years ago at CROI researchers started reporting in very small amounts of data that patients were experiencing premature aging reflected by onset of senescence and ongoing activation. Outside of HIV the elderly develop senescence, where the immune system becomes weakened and encourages onset of comorbidities. In HIV ongoing virus is present in some form in patients even with undetectable viral load, activation. All this contributes to inflammation. At the 2009 CROI there was quite a lot of new information that inflammation is associated with onset of heart disease, cognitive impairment. At this year's 2010 CROI there was an explosion of studies on aging and inflammation; studies finding patients are experiencing ongoing inflammation and it's associated with HCV, heart disease, kidney function, brain disease. At CROI there were several studies reporting that ART intensification with the CCR5 drug maraviroc or the integrase raltegravir appeared to reduce activation & perhaps inflammation. So now this has become I think the most important area in HIV. The issue of aging and inflammation are getting traction among academic researchers, drug companies and at the NIH and the Division of AIDS within the NIH. But a lot more research is needed as we have just begin to scrtach the surface in trying to understand the problem and if we can intervene to prevent or ameliorate the problem. Of special note is, what causes inflammation, because inflammation merely reflects a problem below the surface. There is quite a bit of research suggestion the most significant problems might be senescence and ongoin activation, causing inflammation. There appear to be many other potential contributing factors including mitochondrial toxicity, a patient history of substance abuse poor lifestyle behaviors, ARTs, and perhaps others. SO, we need a very focused targeted and dedicated effort by the NIH to address these questions. We need funding dedicated by the NIH to aging & HIV and we need support from the broad community to influence the NIH to do this.

Inflammation, Aging & Brain Dysfunction

Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function - (04/03/10)NEUROLOGY March 2010;"we found higher hs-CRP values to be associated with worse performance in executive functions, including tests of psychomotor speed and attention. Other cognitive domains, i.e., memory and linguistic skills, showed no association with CRP".....Serum hs-CRP levels were higher in subjects with a history of hypertension....Higher high-density lipoprotein levels were associated with lower hs-CRP ....."The phenomenon of cognitive aging is characterized by deficits in executive functions, information processing speed, and attention. Histopathologic studies showed an age-related decrease of myelin and the number of myelinated fibers.31 In vivo, DTI appears to be the most sensitive imaging measure"....."Recent interventional studies using antiinflammatory drugs such as aspirin and statins to lower circulating CRP levels showed a significant reduction in the incidence of cardiovascular events.36,37 There is also evidence of a beneficial effect of lifestyle interventions on cognitive functions, such as physical activity and body weight control,38,39 which have been shown to decrease circulating CRP levels.38,39 Whether lowering of CRP can also prevent cognitive decline and/or microstructural white matter alterations needs to be addressed in upcoming clinical trials."

Subjective memory impairment predicted conversion to dementia or Alzheimer's disease as early as three years before diagnosis, according to a German study.

Subjective memory impairment, plus worry about the impairment, more than tripled the likelihood of conversion to any dementia or Alzheimer's disease at follow-up 18 months and three years later, Frank Jessen, MD, of the University of Bonn, and colleagues wrote in the April Archives of General Psychiatry.

Patients with subjective memory impairment at baseline and mild cognitive impairment 18 months later had almost 10 times the risk of any dementia at three years, and almost 20 times the risk of Alzheimer's disease, compared to patients without subjective memory impairment at baseline or mild cognitive impairment at the first follow-up.

"Because subjects with impairment on baseline testing were excluded in this study, our data support the concept of subjective memory impairment as a pre-mild cognitive impairment condition in Alzheimer's disease."

The anticipated development of disease-modifying treatment for Alzheimer's disease has fueled research into identification of at-risk and prodromal syndromes for dementia.

The research has already led to identification of mild cognitive impairment as an at-risk condition associated with an annual conversion rate for dementia of 10% to 20%, the authors wrote.

Mild cognitive impairment reflects neuropsychological test performance that falls below age-, sex-, and education-adjusted norms. However, studies have shown that Alzheimer's disease-related brain pathology begins to evolve several years before the onset of mild cognitive impairment.

"Recently, the temporal association of this pre-mild cognitive impairment cognitive decline with the occurrence of cognitive complaints in subjects with subjective dementia has been demonstrated, suggesting that initial worsening of cognitive performance is already experienced by affected individuals," the authors wrote.

To examine the association between subjective memory impairment and dementia, investigators analyzed data from an ongoing cohort study.

They identified study participants 75 or older who did not have dementia in the clinical judgment of their primary care physicians. All participants had reported at least one visit with their primary care physicians within the past 12 months. Nursing-home residents, patients who had only at-home visits with physicians, and deaf or blind patients were excluded.

The baseline sample comprised 3,327 study participants. Of those, 2,820 participated in an at-home follow-up at 18 months, and 2,487 participated in the three-year, at-home follow-up.

The follow-up visits included interviews by trained psychologists and a battery of neuropsychologic tests. At the 18-month follow-up, participants were asked: Do you feel like your memory is becoming worse? Participants had three possible answers: NoYes, but this does not worry meYes, this worries meMild cognitive impairment and dementia were defined according to accepted diagnostic criteria.Of 2,415 participants included in the analysis, 1,027 had no subjective memory impairment at baseline, while 1,006 had subjective memory impairment without worry, and 382 had subjective memory impairment with worry.

Investigators found 110 cases of conversion to any type of dementia at the first or second follow-up visit, 54 cases of conversion to dementia in Alzheimer's disease, and 26 cases of vascular dementia.Among patients without subjective memory impairment at baseline, 26 had conversion to any dementia and nine each had conversion to dementia in Alzheimer's disease and vascular dementia.

Study participants without subjective memory impairment at baseline or mild cognitive impairment at the first follow-up served as the reference group.

As compared with the reference group, subjective memory impairment without worry almost doubled the likelihood of conversion to any dementia (HR 1.83, 95% CI 1.12 to 2.99) and tripled the risk of conversion to dementia in Alzheimer's disease (HR 3.04, 95% CI 1.36 to 6.81).

Subjective memory impairment with worry was associated with a hazard ratio of 3.53 for conversion to any dementia (95% CI 2.07 to 6.03) and a hazard ratio of 6.54 for conversion to dementia in Alzheimer's disease (95% CI 2.82 to 15.20).

Participants with mild cognitive impairment had even higher rates of dementia conversion. As compared with the reference group, participants with no subjective memory impairment at baseline and mild cognitive impairment at the first follow-up visit had a four-fold increased risk of conversion to any dementia at the second follow-up visit (HR 4.41, 95% CI 1.44 to 13.48) and almost a six-fold greater risk of conversion to dementia in Alzheimer's disease (HR 5.74, 95% CI 1.09 to 30.16).

Participants with subjective memory impairment at baseline and mild cognitive impairment at the first follow-up visit had the greatest risk of dementia conversion at the second follow-up visit: A nine-fold increased hazard for any dementia (HR 8.92, 95% CI 3.69 to 21.60) and a 19-fold increased hazard for conversion to dementia in Alzheimer's disease (HR 19.33, 95% CI 5.29 to 70.81).

The presence of amnestic mild cognitive impairment further increased the likelihood of dementia conversion.

Limitations of the study, according to the authors, included small numbers in some subgroups due to definitions used, use of a scoring system that did not allow in-depth testing, and self-report of subjective memory impairment, which was therefore not assessed in detail.

"In summary, we found that effective and adherent HAART use was significantly associated with a reduced burden of HPV infection and SILs among HIV‐positive women. These protective effects may help explain why age‐specific cervical cancer rates have not increased despite the greater survival of HIV‐positive women during the HAART era. However, the overall public health burden of cervical cancer in HIV‐positive patients could grow as this population increasingly enters older age groups, which have higher cervical cancer rates......The average prevalence of oncogenic HPV infection decreased 36% in adherent women (from 22% before to 14% after HAART initiation) and 12% in nonadherent individuals (from 24% before to 21% after HAART initiation)....adherent women had a highly significant reduction in oncogenic HPV prevalence following their initiation of HAART (odds ratio [OR] [after vs before], 0.60 [95% confidence interval {CI}, 0.44–0.81]; p=.001), whereas nonadherent HAART use was not significantly associated with a change in oncogenic HPV prevalence (Table 2). A direct comparison of rates in adherent women versus nonadherent women after HAART initiation suggested an about 30% reduction in oncogenic HPV prevalence related to adherence (OR [adherent vs nonadherent], 0.70 [95% CI, 0.48–1.01]; p=.06)......Adherent HAART use was also associated with a reduction in the incident detection rate of oncogenic HPV infection. Specifically, the rate of incident detection decreased 33%......Our major end point was oncogenic HPV–positive SILs (oncHPV+ SILs), lesions that are thought to have the potential to result in tumors. Adherent users had a significant reduction in oncHPV+ SIL prevalence after HAART initiation.....there was a significant relationship between adherent HAART use and the rate of oncHPV+ SIL clearance...which was significantly greater than the oncHPV+ SIL clearance rate observed among nonadherent women.....The average prevalence of oncogenic HPV infection decreased 20% in patients using effective HAART, from 20% before to 14% after HAART initiation, and did not decrease but actually increased slightly in those using ineffective HAART, from 22% before to 24% after HAART initiation."

"The results of this study suggest that it is common for anal and cervical HPV infections to occur consecutively. The high degree of genotype‐specific concordance indicates a common source of infection, such as vaginal and anal intercourse with the same infected partner(s), although alternate routes of transmission, including nonpenetrative sexual contact and autoinoculation, need to be explored. The clinical consequences of our observations include higher rates of genital warts and anal and cervical cancers among HPV‐infected women, through the spread of infection within the anogenital area, although cytologic information was not included in this analysis. These results provide at least a partial basis for the finding that women with cervical intraepithelial neoplasia or cancer are at higher risk of anal cancer. Although anal cytologic screening is cost‐effective in HIV‐infected men who have sex with men [30], studies of the efficacy of this approach in other HR groups have not been conducted."

11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento

Mark Mascolini

More than half of 1000 HIV-infected people surveyed at a large HIV clinic in Barcelona use complementary or alternative therapies that they believe help them control their infection or its symptoms [1]. Better educated people were more than twice as likely to use an alternative therapy, and only half who used such remedies asked their HIV physicians about them. Many of the agents used have some impact on the CYP3A4 enzyme, which is involved in the metabolism of many key antiretrovirals.

Jose Molto and colleagues at the University Hospital Germans Trias i Pujol gave a self-administered questionnaire to 1000 HIV-infected adults attending the HIV clinic pharmacy department. The researchers matched results with medical records from the clinic.

The group's age averaged 43.2 years (+/- 8.5 standard deviation), 75.4% were men, 88% were Caucasian, and 73.7% had a high school or college education. But only 57.4% had a job, and 49.7% had an income below 1000 Euros per month. The study group averaged 12.6 years (+/- 7.5) since their HIV diagnosis, 43.1% were gay men, 88.7% were taking antiretrovirals, 79.9% had a viral load below 50 copies, and 60.7% had non-HIV symptoms. The group's CD4 count averaged 572 (+/- 314).

Of the 1000 survey respondents, 584 acknowledged using some alternative therapy, and most used more than one: the median number of unlicensed remedies was 3 (interquartile range 2 to 7). Of the 584 people using alternative remedies, only 324 (55.5%) had discussed their use with their HIV clinician, and only 124 (21.2%) had been monitored for potential interactions between such agents and antiretrovirals.

More than 400 people used dietary supplements, and more than 300 used herbal remedies. The most frequently used agents that may interfere with antiretroviral metabolism were garlic (71 people, CYP3A4 induction), ginseng (67 people, CYP3A4 inhibition), Echinacea species (60 people, CYP3A4 induction and/or inhibition), and milk thistle (36 people, CYP3A4 induction).

Five factors independently raised the chance of using alternative therapies:

Molto and coworkers recommended that HIV patients and physicians "should be sensitized to the potential risks . . . of complementary or alternative medicine, and especially herbal remedies, and encouraged to discuss such therapies openly during clinical visits."